Triazole N-Linked Carbamoyl Cyclohexyl Acids as LPA Antagonists

ABSTRACT

The present invention provides compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein all the variables are as defined herein. These compounds are selective LPA receptor inhibitors.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Pat. Application No.17/224,161, filed Apr. 07, 2021, now allowed, which is a continuation ofU.S. Pat. Application No. 16/744,303, filed Jan. 16, 2020, U.S. Pat. No.11,008,300, which is a continuation of U.S. Pat. Application No.16/223,169, filed Dec. 18, 2018, U.S. Pat. No. 10,662,172, which claimsthe priority benefit of U.S. Provisional Application No. 62/607,399,filed Dec. 19, 2017; the contents of which are herein incorporated byreference in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel substituted triazole compounds,compositions containing them, and methods of using them, for example,for the treatment of disorders associated with one or more of thelysophosphatidic acid (LPA) receptors.

BACKGROUND OF THE INVENTION

Lysophospholipids are membrane-derived bioactive lipid mediators, ofwhich one of the most medically important is lysophosphatidic acid(LPA). LPA is not a single molecular entity but a collection ofendogenous structural variants with fatty acids of varied lengths anddegrees of saturation (Fujiwara et al., J Biol. Chem., 2005, 280,35038-35050). The structural backbone of the LPAs is derived fromglycerol-based phospholipids such as phosphatidylcholine (PC) orphosphatidic acid (PA).

The LPAs are bioactive lipids (signaling lipids) that regulate variouscellular signaling pathways by binding to the same class of7-transmembrane domain G protein-coupled (GPCR) receptors (Chun, J.,Hla, T., Spiegel, S., Moolenaar, W., Editors, LysophospholipidReceptors: Signaling and Biochemistry, 2013, Wiley; ISBN:978-0-470-56905-4 & Zhao, Y. et al, Biochim. Biophys. Acta (BBA)-Mol.Cell Biol. Of Lipids, 2013, 1831, 86-92). The currently known LPAreceptors are designated as LPA₁, LPA₂, LPA₃, LPA₄, LPA₅ and LPA₆ (Choi,J. W., Annu. Rev. Pharmacol. Toxicol., 2010, 50, 157-186; Kihara, Y., etal, Br. J. Pharmacol., 2014, 171, 3575-3594).

The LPAs have long been known as precursors of phospholipid biosynthesisin both eukaryotic and prokaryotic cells, but the LPAs have emerged onlyrecently as signaling molecules that are rapidly produced and releasedby activated cells, notably platelets, to influence target cells byacting on specific cell-surface receptors (see, e.g., Moolenaar et al.,BioEssays, 2004, 26, 870-881, and van Leewen et al., Biochem. Soc.Trans., 2003, 31, 1209-1212). Besides being synthesized and processed tomore complex phospholipids in the endoplasmic reticulum, LPAs can begenerated through the hydrolysis of pre-existing phospholipids followingcell activation; for example, the sn-2 position is commonly missing afatty acid residue due to deacylation, leaving only the sn-1 hydroxylesterified to a fatty acid. Moreover, a key enzyme in the production ofLPA, autotaxin (lysoPLD/NPP2), may be the product of an oncogene, asmany tumor types up-regulate autotaxin (Brindley, D., J. Cell Biochem.2004, 92, 900-12). The concentrations of LPAs in human plasma & serum aswell as human bronchoalveolar lavage fluid (BALF) have been reported,including determinations made using sensitive and specific LC/MS &LC/MS/MS procedures (Baker et al. Anal. Biochem., 2001, 292, 287-295;Onorato et al., J. Lipid Res., 2014, 55, 1784-1796).

LPA influences a wide range of biological responses, ranging frominduction of cell proliferation, stimulation of cell migration andneurite retraction, gap junction closure, and even slime mold chemotaxis(Goetzl, et al., Scientific World J., 2002, 2, 324-338; Chun, J., Hla,T., Spiegel, S., Moolenaar, W., Editors, Lysophospholipid Receptors:Signaling and Biochemistry, 2013, Wiley; ISBN: 978-0-470-56905-4). Thebody of knowledge about the biology of LPA continues to grow as more andmore cellular systems are tested for LPA responsiveness. For instance,it is now known that, in addition to stimulating cell growth andproliferation, LPAs promote cellular tension and cell-surfacefibronectin binding, which are important events in wound repair andregeneration (Moolenaar et al., BioEssays, 2004, 26, 870-881). Recently,anti-apoptotic activity has also been ascribed to LPA, and it hasrecently been reported that PPARγ is a receptor/target for LPA (Simon etal., J. Biol. Chem., 2005, 280, 14656-14662).

Fibrosis is the result of an uncontrolled tissue healing process leadingto excessive accumulation and insufficient resorption of extracellularmatrix (ECM) which ultimately results in end-organ failure (Rockey, D.C., et al., New Engl. J. Med., 2015, 372, 1138-1149). The LPA₁ receptorhas been reported to be over-expressed in idiopathic pulmonary fibrosis(IPF) patients. LPA₁ receptor knockout mice were protected frombleomycin-induced lung fibrosis (Tager et al., Nature Med., 2008, 14,45-54). The LPA₁ antagonist BMS-986020 was shown to significantly reducethe rate of FVC (forced vital capacity) decline in a 26-week clinicaltrial in IPF patients (Palmer et al., Chest, 2018, 154, 1061-1069). LPApathway inhibitors (e.g. an LPA₁ antagonist) were shown to bechemopreventive anti-fibrotic agents in the treatment of hepatocellularcarcinoma in a rat model (Nakagawa et al., Cancer Cell, 2016, 30,879-890).

Thus, antagonizing the LPA₁ receptor may be useful for the treatment offibrosis such as pulmonary fibrosis, hepatic fibrosis, renal fibrosis,arterial fibrosis and systemic sclerosis, and thus the diseases thatresult from fibrosis (pulmonary fibrosis-Idiopathic Pulmonary Fibrosis[IPF], hepatic fibrosis-Non-alcoholic Steatohepatitis [NASH], renalfibrosis-diabetic nephropathy, systemic sclerosis-scleroderma, etc.).

SUMMARY OF THE INVENTION

The present invention provides novel substituted triazole compoundsincluding stereoisomers, tautomers, and pharmaceutically acceptablesalts or solvates thereof, which are useful as antagonists against oneor more of the lysophosphatidic acid (LPA) receptors, especially theLPA₁ receptor.

The present invention also provides processes and intermediates formaking the compounds of the present invention.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts or solvates thereof.

The compounds of the invention may be used in the treatment ofconditions in which LPA plays a role.

The compounds of the present invention may be used in therapy.

The compounds of the present invention may be used for the manufactureof a medicament for the treatment of a condition in which inhibition ofthe physiological activity of LPA is useful, such as diseases in whichan LPA receptor participates, is involved in the etiology or pathologyof the disease, or is otherwise associated with at least one symptom ofthe disease.

In another aspect, the present invention is directed to a method oftreating fibrosis of organs (liver, kidney, lung, heart and the like aswell as skin), liver diseases (acute hepatitis, chronic hepatitis, liverfibrosis, liver cirrhosis, portal hypertension, regenerative failure,non-alcoholic steatohepatitis (NASH), liver hypofunction, hepatic bloodflow disorder, and the like), cell proliferative disease [cancer (solidtumor, solid tumor metastasis, vascular fibroma, myeloma, multiplemyeloma, Kaposi’s sarcoma, leukemia, chronic lymphocytic leukemia (CLL)and the like) and invasive metastasis of cancer cell, and the like],inflammatory disease (psoriasis, nephropathy, pneumonia and the like),gastrointestinal tract disease (irritable bowel syndrome (IBS),inflammatory bowel disease (IBD), abnormal pancreatic secretion, and thelike), renal disease, urinary tract-associated disease (benign prostatichyperplasia or symptoms associated with neuropathic bladder disease,spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis,symptoms derived from diabetes, lower urinary tract disease (obstructionof lower urinary tract, and the like), inflammatory disease of lowerurinary tract, dysuria, frequent urination, and the like), pancreasdisease, abnormal angiogenesis-associated disease (arterial obstructionand the like), scleroderma, brain-associated disease (cerebralinfarction, cerebral hemorrhage, and the like), neuropathic pain,peripheral neuropathy, and the like, ocular disease (age-related maculardegeneration (AMD), diabetic retinopathy, proliferativevitreoretinopathy (PVR), cicatricial pemphigoid, glaucoma filtrationsurgery scarring, and the like).

In another aspect, the present invention is directed to a method oftreating diseases, disorders, or conditions in which activation of atleast one LPA receptor by LPA contributes to the symptomology orprogression of the disease, disorder or condition. These diseases,disorders, or conditions may arise from one or more of a genetic,iatrogenic, immunological, infectious, metabolic, oncological, toxic,surgical, and/or traumatic etiology.

In another aspect, the present invention is directed to a method oftreating renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterialfibrosis and systemic sclerosis comprising administering to a patient inneed of such treatment a compound of the present invention as describedabove.

In one aspect, the present invention provides methods, compounds,pharmaceutical compositions, and medicaments described herein thatcomprise antagonists of LPA receptors, especially antagonists of LPA₁.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore, preferably one to two other agent(s).

These and other features of the invention will be set forth in expandedform as the disclosure continues.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Invention

In one aspect, the present invention provides, inter alia, compounds ofFormula (I):

or a stereoisomer, tautomer, or pharmaceutically acceptable salt orsolvate thereof, wherein:

-   X¹, X², X³, and X⁴ are each independently CR⁶ or N; provided that no    more than two of X¹, X², X³, or X⁴ are N;

-   one of Q¹, Q², and Q³ is NR⁵, and the other two are N; and the    dashed circle denotes optional bond forming an aromatic ring;

-   Y¹ is O or NR³;

-   Y² is

-   

-   

-   

-   Y³ is O or NR^(4a); provided that (1) Y¹ and Y³ are not both O,    and (2) when Y² is C(O), Y¹ is not O;

-   L is a covalent bond or C₁₋₄ alkylene substituted with 0 to 4 R⁷;

-   R¹ is (—CH₂)_(a)R⁹;

-   a is an integer of 0 or 1;

-   R² is each independently halo, cyano, hydroxyl, amino, C₁₋₆ alkyl,    C₃₋₆ cycloalkyl, C₄₋₆ heterocyclyl, C₁₋₆ alkylamino, C₁₋₆ haloalkyl,    C₁₋₆ hydroxyalkyl, C₁₋₆ aminoalkyl, C₁₋₆ alkoxy, alkoxyalkyl,    haloalkoxyalkyl, or haloalkoxy;

-   n is an integer of 0, 1, or 2;

-   R³ and R^(4a) are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆    haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ aminoalkyl, alkoxyalkyl,    haloalkoxyalkyl, C₁₋₆ alkoxy, or haloalkoxy;

-   R⁴ is C₁₋₁₀ alkyl, C₁₋₁₀ deuterated alkyl (fully or partially    deuterated), C₁₋₁₀ haloalkyl, C₁₋₁₀ alkenyl, C₃₋₈ cycloalkyl, 6 to    10-membered aryl, 3 to 8-membered heterocyclyl, -(C₁₋₆    alkylene)-(C₃₋₈ cycloalkyl), -(C₁₋₆ alkylene)-(6 to 10-membered    aryl), -(C₁₋₆ alkylene)-(3 to 8-membered heterocyclyl), or -(C₁₋₆    alkylene)-(5 to 6-membered heteroaryl); wherein each of the alkyl,    alkenyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, by itself    or as part of other moiety, is independently substituted with 0 to 3    R⁸; or alternatively, R³ and R⁴, taken together with the atoms to    which they are attached, form a 4- to 9-membered heterocyclic ring    moiety which is substituted with 0 to 3 R⁸;

-   R⁵ is hydrogen, C₁₋₆ alkyl, alkylamino, haloalkyl, hydroxyalkyl,    aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;

-   R⁶ is hydrogen, halo, cyano, hydroxyl, amino, C₁₋₆ alkyl,    alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,    haloalkoxyalkyl, alkoxy, or haloalkoxy;

-   R⁷ is halo, oxo, cyano, hydroxyl, amino, C₁₋₆ alkyl, C₃₋₆    cycloalkyl, C₄₋₆ heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl,    aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;

-   R⁸ are each independently deuterium, halo, hydroxyl, amino, cyano,    C₁₋₆ alkyl, C₁₋₆ deuterated alkyl (fully or partially deuterated),    C₂₋₆ alkenyl, C₂₋₆ alkynyl, alkylamino, haloalkyl, hydroxyalkyl,    aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, -CHO,    phenyl, or 5 to 6 membered heteroaryl; or alternatively, two R⁸,    taken together with the atoms to which they are attached, form a 3    to 6-membered carbocyclic ring or a 3 to 6-membered heterocyclic    ring each of which is independently substituted with 0 to 3 R¹²;

-   R⁹ is selected from —CN, —C(O)OR¹⁰, —C(O)NR^(11a)R^(11b),

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   R^(e) is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, haloalkyl, hydroxyalkyl,    aminoalkyl, alkoxyalkyl, or haloalkoxyalkyl;

-   R¹⁰ is hydrogen or C₁₋₁₀ alkyl;

-   R^(11a) and R^(11b)) are each independently hydrogen, C₁₋₆ alkyl,    C₃₋₆ cycloalkyl, C₄₋₆ heterocyclyl, alkylamino, haloalkyl,    hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or    haloalkoxy; and

-   R¹² is halo, cyano, hydroxyl, amino, C₁₋₆ alkyl, alkylamino,    haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl,    alkoxy, haloalkoxy, phenyl, or 5 to 6 membered heteroaryl.

In one embodiment of Formula (I), R⁸ are each independently deuterium,halo, hydroxyl, amino, cyano, C₁₋₆ alkyl, C₁₋₆ deuterated alkyl (fullyor partially deuterated), C₂₋₆ alkenyl, C₂₋₆ alkynyl, alkylamino,haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl,alkoxy, haloalkoxy, phenyl, or 5 to 6 membered heteroaryl; oralternatively, two R⁸, taken together with the atoms to which they areattached, form a 3 to 6-membered carbocyclic ring or a 3 to 6-memberedheterocyclic ring each of which is independently substituted with 0 to 3R¹².

In one embodiment of Formula (I), X¹ is CR⁶, where R⁶ is hydrogen orC₁₋₄ alkyl, e.g., methyl.

In any one of the preceding embodiments of Formula (I), the

moiety is

In any one of the preceding embodiments of Formula (I), the

moiety is selected from

Y⁴ is O or NH.

In any one of the preceding embodiments of Formula (I), L is a covalentbond or methylene.

In any one of the preceding embodiments of Formula (I), n is 0 or 1.

In any one of the preceding embodiments of Formula (I), R⁵ is C₁₋₄alkyl. In one embodiment, R^(5a) is methyl.

In any one of the preceding embodiments of Formula (I), R¹ is CO₂H.

In any one of the preceding embodiments of Formula (I), R³ and R⁴, takentogether with the N and O to which they are attached, form a 5 to7-membered heterocyclic ring moiety which is substituted with 1 R⁸; andR⁸ is benzyl or phenyl.

In any one of the preceding embodiments of Formula (I), R⁴ is C₁₋₁₀alkyl, C₁₋₁₀ haloalkyl, C₃₋₆ cycloalkyl, -(C₁₋₄ alkylene)-(C₃₋₆cycloalkyl), -(C₁₋₄ alkylene)-(C₁₋₆ alkoxy), or -(C₁₋₄ alkylene)-phenyl;wherein each of the alkyl, alkylene, cycloalkyl, and phenyl, by itselfor as part of other moiety, is independently substituted with 0 to 3 R⁸;and R⁸ is each independently halo, hydroxyl, amino, cyano, C₁₋₆ alkyl,alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,haloalkoxyalkyl, alkoxy, or haloalkoxy; or alternatively, two R⁸, takentogether with the atom(s) to which they are attached, form a 3 to6-membered carbocyclic ring. The alkyl and alkylene are eachindependently straight-chain or branched; and the methylene and thephenyl moieties of the benzyl are each independently substituted with 0to 3 R⁸.

In any one of the preceding embodiments of Formula (I), the compound isrepresented by Formula (IIa), (IIb), (IIc), (IId), (IIe), or (IIf):

or a stereoisomer, tautomer, or pharmaceutically acceptable salt orsolvate thereof, wherein:

-   each R^(7a) is independently hydrogen, halo, oxo, cyano, hydroxyl,    amino, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₄₋₆ heterocyclyl, alkylamino,    haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl,    alkoxy, or haloalkoxy;-   f is an integer of 0, 1, or 2;-   R³ is hydrogen or C₁₋₄ alkyl;-   R⁴ is C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, 6 to 10-membered aryl, -(C₁₋₆    alkylene)-(C₃₋₈ cycloalkyl), or -(C₁₋₆ alkylene)-(6 to 10-membered    aryl); wherein each of the alkyl, alkenyl, cycloalkyl, aryl,    heterocyclyl, and heteroaryl, by itself or as part of other moiety,    is independently substituted with 0 to 3 R⁸; or alternatively, R³    and R⁴, taken together with the N and O to which they are attached,    form a 4 to 6-membered heterocyclic ring moiety which is substituted    with 0 to 3 R⁸;-   n is 0 or 1; and-   R¹, R², R⁵, R^(5a), R⁸; X¹, X², X³, X⁴, and Z are the same as    defined above.

In one embodiment of Formula (IIa) or (IIb), the heterocyclic ringformed by R³ and R⁴ is substituted with 1 phenyl or 1 benzyl.

In any one of the preceding embodiments of Formula (IIa) or (IIb), R¹ isCO₂H.

In any one of the preceding embodiments of Formula (IIa) or (IIb), X¹ isCR⁶, where R⁶ is hydrogen or C₁₋₄ alkyl. In one embodiment, X¹ is CH orCCH₃.

In any one of the preceding embodiments of Formula (IIa) or (IIb), X³ isN.

In any one of the preceding embodiments of Formula (IIa) or (IIb), X¹ isCR⁶, where each R⁶ is independently hydrogen, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxyalkyl. In another embodiment, X¹, X², X³, and X⁴are CH.

In any one of the preceding embodiments of Formula (IIa) or (IIb), the

moiety is selected from

-   R^(6a) is each independently halo, cyano, hydroxyl, amino, C₁₋₆    alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,    haloalkoxyalkyl, alkoxy, or haloalkoxy; and-   d is an integer of 0, 1, or 2.

In any one of the preceding embodiments of Formula (IIa) or (IIb), the

moiety is selected from

R⁶ is each independently hydrogen, halo, cyano, hydroxyl, amino, C₁₋₆alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,haloalkoxyalkyl, alkoxy, or haloalkoxy.

In any one of the preceding embodiments of Formula (IIa) or (IIb), f is0 or 1. In one embodiment, R^(7a) is hydrogen.

In any one of the preceding embodiments of Formula (IIa) or (IIb), thecompound is represented by Formula (IIIa) or Formula (IIIb):

or a stereoisomer, tautomer, or pharmaceutically acceptable salt orsolvate thereof, wherein: R^(2a) is hydrogen, chloro, fluoro, or C₁₋₄alkyl; R³ is hydrogen or C₁₋₆ alkyl; and R¹, R⁴, X¹, X², X³, and X⁴ arethe same as defined above.

In one embodiment of Formula (IIIa) or (IIIb), the

moiety is selected from

In any one of the preceding embodiments of Formula (IIIa) or (IIIb), R¹is CO₂H.

In any one of the preceding embodiments of Formula (IIIa) or (IIIb), the

moiety is selected from

R⁶ is each independently hydrogen, CH₃, CH₂CH₃, CH₂OCH₃, CHF₂, or CF₃.

In any one of the preceding embodiments of Formula (IIIb), the compoundis represented by Formula (IV):

or a stereoisomer, tautomer, or pharmaceutically acceptable salt orsolvate thereof, wherein: R^(2a) is hydrogen, chloro, fluoro, or C₁₋₄alkyl; R³ is hydrogen or C₁₋₆ alkyl; and R⁶ and R⁴ are the same asdefined above. In one embodiment, R⁶ is hydrogen, C₁₋₆ alkyl,alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,haloalkoxyalkyl, alkoxy, or haloalkoxy. In another embodiment, R⁶ ismethyl or ethyl. In one embodiment, R⁴ is C₁₋₁₀ alkyl, -(C₁₋₆alkylene)₀₋₁-phenyl, or -(C₁₋₆ alkylene)₀₋₁-(C₃₋₈ cycloalkyl). Inanother embodiment, R⁴ is C₁₋₆ alkyl, -(CH₂)₀₋₂-(C₃₋₆ cycloalkyl),-(CHCH₃)-(C₃₋₆ cycloalkyl), -(CH₂)₁₋₂-phenyl, or -(CHCH₃)-phenyl.

In any one of the preceding embodiments of Formula (IIIa) or (IIIb), R⁴is C₃₋₁₀ alkyl, C₃₋₁₀ haloalkyl, C₃₋₆ cycloalkyl, phenyl, -(C₁₋₄alkylene)-(C₁₋₃ alkoxy), -(C₁₋₄ alkylene)-(C₃₋₆ cycloalkyl), or benzyl;wherein the alkyl, alkylene, cycloalkyl, and benzyl are eachindependently substituted with 0 to 3 R⁸; and R⁸ is each independentlyhalo, C₁₋₆ alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl,alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; or alternatively,two R⁸, taken together with the atoms to which they are attached, form a3 to 6-membered carbocyclic ring. The alkyl and alkylene are eachindependently straight-chain or branched; and the methylene and thephenyl moieties of the benzyl are each independently substituted with 0to 3 R⁸.

In any one of the preceding embodiments of Formula (IIIa) or (IIIb), R⁴is C₃₋₁₀ alkyl, C₃₋₁₀ haloalkyl, cyclobutyl, cyclopentyl,-(CH₂)₁₋₂-(C₁₋₃ alkoxy), -(CHR^(8a))₁₋₂-cyclopropyl,-(CHR^(8a))₁₋₂-cyclobutyl, or -(CHR^(8a))₁₋₂-phenyl; wherein thecyclopropyl, cyclobutyl, cyclopentyl, and phenyl are each independentlysubstituted with 0 to 3 R⁸; or alternatively, two R⁸, taken togetherwith the atom to which they are attached, form cyclopropyl; R^(8a) iseach independently hydrogen or methyl; and R⁸ is each independently haloor C₁₋₄ alkyl.

In one embodiment of the present invention, the compound is selectedfrom any one of the Examples as described in the specification, or astereoisomer, a tautomer, or a pharmaceutically acceptable salt orsolvate thereof.

In another embodiment of the present invention, the compound is selectedfrom Examples 1 to 240 as described in the specification, or astereoisomer, a tautomer, or a pharmaceutically acceptable salt orsolvate thereof.

In another embodiment of the present invention, the compound is selectedfrom Examples 1 to 145 as described in the specification, or astereoisomer, a tautomer, or a pharmaceutically acceptable salt orsolvate thereof.

In one embodiment of the present invention, the compound is selectedfrom:

or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment of the present invention, the compound is selectedfrom:

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment of the present invention, the compound is selectedfrom:

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment of the present invention, the compound is selectedfrom:

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment of the present invention, the compound is selectedfrom:

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment of the present invention, the compound is selectedfrom:

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment of the present invention, the compound is selectedfrom:

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment of the present invention, the compound is selectedfrom:

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment of the present invention, the compound is selectedfrom:

or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the compounds of the present invention have hLPA₁IC₅₀ values ≤ 5000 nM, using the LPA₁ functional antagonist assay; inanother embodiment, the compounds of the present invention have hLPA₁IC₅₀ values ≤ 1000 nM; in another embodiment, the compounds of thepresent invention have hLPA₁ IC₅₀ values ≤ 500 nM; in anotherembodiment, the compounds of the present invention have hLPA₁ IC₅₀values ≤ 200 nM; in another embodiment, the compounds of the presentinvention have hLPA₁ IC₅₀ values ≤ 100 nM; in another embodiment, thecompounds of the present invention have hLPA₁ IC₅₀ values ≤ 50 nM.

II. Other Embodiments of the Invention

In some embodiments, the compound of Formulas (I), or a pharmaceuticallyacceptable salt thereof, is an antagonist of at least one LPA receptor.In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is an antagonist of LPA₁. In some embodiments,the compound of Formula (I), or a pharmaceutically acceptable saltthereof, is an antagonist of LPA₂. In some embodiments, the compound ofFormula (I), or a pharmaceutically acceptable salt thereof, is anantagonist of LPA₃.

In some embodiments, presented herein are compounds selected from activemetabolites, tautomers, pharmaceutically acceptable salts or solvates ofa compound of Formula (I).

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s).

In another embodiment, the present invention provides a method for thetreatment of a condition associated with LPA receptor mediated fibrosis,comprising administering to a patient in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof. As used herein, the term“patient” encompasses all mammalian species.

In another embodiment, the present invention provides a method oftreating a disease, disorder, or condition associated with dysregulationof lysophosphatidic acid receptor 1 (LPA₁) in a patient in need thereof,comprising administering a therapeutically effective amount of acompound of the present invention, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt or solvate thereof, to the patient. Inone embodiment of the method, the disease, disorder, or condition isrelated to pathological fibrosis, transplant rejection, cancer,osteoporosis, or inflammatory disorders. In one embodiment of themethod, the pathological fibrosis is pulmonary, liver, renal, cardiac,dernal, ocular, or pancreatic fibrosis. In one embodiment of the method,the disease, disorder, or condition is idiopathic pulmonary fibrosis(IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liverdisease (NAFLD), chronic kidney disease, diabetic kidney disease, andsystemic sclerosis. In one embodiment of the method, the cancer is ofthe bladder, blood, bone, brain, breast, central nervous system, cervix,colon, endometrium, esophagus, gall bladder, genitalia, genitourinarytract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral ornasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine,large intestine, stomach, testicle, or thyroid.

In another embodiment, the present invention provides a method oftreating fibrosis in a mammal comprising administering a therapeuticallyeffective amount of a compound of the present invention, or astereoisomer, a tautomer, or a pharmaceutically acceptable salt orsolvate thereof, to the mammal in need thereof. In one embodiment of themethod, the fibrosis is idiopathic pulmonary fibrosis (IPF),nonalcoholic steatohepatitis (NASH), chronic kidney disease, diabetickidney disease, and systemic sclerosis.

In another embodiment, the present invention provides a method oftreating lung fibrosis (idiopathic pulmonary fibrosis), asthma, chronicobstructive pulmonary disease (COPD), renal fibrosis, acute kidneyinjury, chronic kidney disease, liver fibrosis (non-alcoholicsteatohepatitis), skin fibrosis, fibrosis of the gut, breast cancer,pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bonecancer, colon cancer, bowel cancer, head and neck cancer, melanoma,multiple myeloma, chronic lymphocytic leukemia, cancer pain, tumormetastasis, transplant organ rejection, scleroderma, ocular fibrosis,age related macular degeneration (AMD), diabetic retinopathy, collagenvascular disease, atherosclerosis, Raynaud’s phenomenon, or neuropathicpain in a mammal ccomprising administering a therapeutically effectiveamount of a compound of the present invention, or a stereoisomer, atautomer, or a pharmaceutically acceptable salt or solvate thereof, tothe mammal in need thereof.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; and/or (b)relieving the disease-state, i.e., causing regression of the diseasestate. As used herein, “treating” or “treatment” also include theprotective treatment of a disease state to reduce and/or minimize therisk and/or reduction in the risk of recurrence of a disease state byadministering to a patient a therapeutically effective amount of atleast one of the compounds of the present invention or a or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof. Patients may be selected for such protective therapybased on factors that are known to increase risk of suffering a clinicaldisease state compared to the general population. For protectivetreatment, conditions of the clinical disease state may or may not bepresented yet. The protective treatment can be divided into (a) primaryprophylaxis and (b) secondary prophylaxis. Primary prophylaxis isdefined as treatment to reduce or minimize the risk of a disease statein a patient that has not yet presented with a clinical disease state,whereas secondary prophylaxis is defined as minimizing or reducing therisk of a recurrence or second occurrence of the same or similarclinical disease state.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments is itsown independent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

III. Chemistry

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C=C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis-and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

The term “stereoisomer” refers to isomers of identical constitution thatdiffer in the arrangement of their atoms in space. Enantiomers anddiastereomers are examples of stereoisomers. The term “enantiomer”refers to one of a pair of molecular species that are mirror images ofeach other and are not superimposable. The term “diastereomer” refers tostereoisomers that are not mirror images. The term “racemate” or“racemic mixture” refers to a composition composed of equimolarquantities of two enantiomeric species, wherein the composition isdevoid of optical activity.

The symbols “R” and “S” represent the configuration of substituentsaround a chiral carbon atom(s). The isomeric descriptors “R” and “S” areused as described herein for indicating atom configuration(s) relativeto a core molecule and are intended to be used as defined in theliterature (IUPAC Recommendations 1996, Pure and Applied Chemistry,68:2193-2222 (1996)).

The term “chiral” refers to the structural characteristic of a moleculethat makes it impossible to superimpose it on its mirror image. The term“homochiral” refers to a state of enantiomeric purity. The term “opticalactivity” refers to the degree to which a homochiral molecule ornonracemic mixture of chiral molecules rotates a plane of polarizedlight.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. While “alkyl” denotes amonovalent saturated aliphatic radical (such as ethyl), “alkylene”denotes a bivalent saturated aliphatic radical (such as ethylene). Forexample, “C₁ to C₁₀ alkyl” or “C₁₋₁₀ alkyl” is intended to include C₁,C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. “C₁ to C₁₀alkylene” or “C₁₋₁₀ alkylene”, is intended to include C₁, C₂, C₃, C₄,C₅, C₆, C₇, C₈, C₉, and C₁₀ alkylene groups. Additionally, for example,“C₁ to C₆ alkyl” or “C₁₋₆ alkyl” denotes alkyl having 1 to 6 carbonatoms; and “C₁ to C₆ alkylene” or “C₁₋₆ alkylene” denotes alkylenehaving 1 to 6 carbon atoms; and “C₁ to C₄ alkyl” or “C₁₋₄ alkyl” denotesalkyl having 1 to 4 carbon atoms; and “C₁ to C₄ alkylene” or “C₁₋₄alkylene” denotes alkylene having 1 to 4 carbon atoms. Alkyl group canbe unsubstituted or substituted with at least one hydrogen beingreplaced by another chemical group. Example alkyl groups include, butare not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g.,n-pentyl, isopentyl, neopentyl). When “C₀ alkyl” or “C₀ alkylene” isused, it is intended to denote a direct bond. Furthermore, the term“alkyl”, by itself or as part of another group, such as alkylamino,haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl,haloalkoxyalkyl, and haloalkoxy, can be an alkyl having 1 to 4 carbonatoms, or 1 to 6 carbon atoms, or 1 to 10 carbon atoms.

“Heteroalkyl” refers to an alkyl group where one or more carbon atomshave been replaced with a heteroatom, such as, O, N, or S. For example,if the carbon atom of the alkyl group which is attached to the parentmolecule is replaced with a heteroatom (e.g., O, N, or S) the resultingheteroalkyl groups are, respectively, an alkoxy group (e.g., -OCH₃,etc.), an alkylamino (e.g., —NHCH₃, —N(CH₃)₂, etc.), or a thioalkylgroup (e.g., —SCH₃). If a non-terminal carbon atom of the alkyl groupwhich is not attached to the parent molecule is replaced with aheteroatom (e.g., O, N, or S) and the resulting heteroalkyl groups are,respectively, an alkyl ether (e.g., —CH₂CH₂—O—CH₃, etc.), analkylaminoalkyl (e.g., —CH₂NHCH₃, —CH₂N(CH₃)₂, etc.), or a thioalkylether (e.g.,—CH₂—S—CH₃). If a terminal carbon atom of the alkyl group isreplaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkylgroups are, respectively, a hydroxyalkyl group (e.g., —CH₂CH₂—OH), anaminoalkyl group (e.g., —CH₂NH₂), or an alkyl thiol group (e.g.,—CH₂CH₂—SH). A heteroalkyl group can have, for example, 1 to 20 carbonatoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. A C₁-C₆ heteroalkylgroup means a heteroalkyl group having 1 to 6 carbon atoms.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. Forexample, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples ofalkenyl include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and4-methyl-3-pentenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

As used herein, “arylalkyl” (a.k.a. aralkyl), “heteroarylalkyl”“carbocyclylalkyl” or “heterocyclylalkyl” refers to an acyclic alkylradical in which one of the hydrogen atoms bonded to a carbon atom,typically a terminal or sp³ carbon atom, is replaced with an aryl,heteroaryl, carbocyclyl, or heterocyclyl radical, respectively. Typicalarylalkyl groups include, but are not limited to, benzyl,2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. The arylalkyl, heteroarylalkyl,carbocyclylalkyl, or heterocyclylalkyl group can comprise 4 to 20 carbonatoms and 0 to 5 heteroatoms, e.g., the alkyl moiety may contain 1 to 6carbon atoms.

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group, wherein said phenylgroup may optionally be substituted with 1 to 5 groups, preferably 1 to3 groups, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃,OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, andCO₂CH₃. “Benzyl” can also be represented by formula “Bn”.

The term “alkoxy” or “alkyloxy” refers to an -O-alkyl group. “C₁ to C₆alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intended to include C₁, C₂,C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxy groups include, but arenot limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), and t-butoxy. Similarly, “alkylthio” or “thioalkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through a sulphur bridge; for example, methyl-S-and ethyl-S-.

The term “alkanoyl” or “alkylcarbonyl” as used herein alone or as partof another group refers to alkyl linked to a carbonyl group. Forexample, alkylcarbonyl may be represented by alkyl-C(O)-. “C₁ to C₆alkylcarbonyl” (or alkylcarbonyl), is intended to include C₁, C₂, C₃,C₄, C₅, and C₆ alkyl-C(O)- groups.

The term “alkylsulfonyl” or “sulfonamide” as used herein alone or aspart of another group refers to alkyl or amino linked to a sulfonylgroup. For example, alkylsulfonyl may be represented by —S(O)₂R′, whilesulfonamide may be represented by —S(O)₂NR^(c)R^(d). R′ is C₁ to C₆alkyl; and R^(c) and R^(d) are the same as defined below for “amino”.

The term “carbamate” as used herein alone or as part of another grouprefers to oxygen linked to an amido group. For example, carbamate may berepresented by N(R^(c)R^(d))—C(O)—O—, and R^(c) and R^(d) are the sameas defined below for “amino”.

The term “amido” as used herein alone or as part of another group refersto amino linked to a carbonyl group. For example, amido may berepresented by N(R^(c)R^(d))—C(O)—, and R^(c) and R^(d) are the same asdefined below for “amino”.

The term “amino” is defined as —NR^(c1)R^(c2), wherein R^(c1) and R^(c2)are independently H or C₁₋₆ alkyl; or alternatively, R^(c1) and R^(c2),taken together with the atoms to which they are attached, form a 3- to8-membered heterocyclic ring which is optionally substituted with one ormore group selected from halo, cyano, hydroxyl, amino, oxo, C₁₋₆ alkyl,alkoxy, and aminoalkyl. When R^(c1) or R^(c2) (or both of them) is C₁₋₆alkyl, the amino group can also be referred to as alkylamino. Examplesof alkylamino group include, without limitation, methylamino,ethylamino, propylamino, isopropylamino and the like. In one embodiment,amino is —NH₂.

The term “aminoalkyl” refers to an alkyl group on which one of thehydrogen atoms is replaced by an amino group. For example, aminoalkylmay be represented by N(R^(c1)R^(c2))-alkylene-. “C₁ to C₆” or “C₁₋₆”aminoalkyl” (or aminoalkyl), is intended to include C₁, C₂, C₃, C₄, C₅,and C₆ aminoalkyl groups.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chlorine, bromine, fluorine, and iodine, with chlorineor fluorine being preferred.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with one or more halogens. “C₁ to C₆haloalkyl” or “C₁₋₆ haloalkyl” (or haloalkyl), is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkyl groups. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms. The term “polyhaloalkyl” as used herein refers to an“alkyl” group as defined above which includes from 2 to 9, preferablyfrom 2 to 5, halo substituents, such as F or Cl, preferably F, such aspolyfluoroalkyl, for example, CF₃CH₂, CF₃ or CF₃CF₂CH₂.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁ to C₆ haloalkoxy” or “C₁₋₆ haloalkoxy”,is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups.Examples of haloalkoxy include, but are not limited to,trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.Similarly, “haloalkylthio” or “thiohaloalkoxy” represents a haloalkylgroup as defined above with the indicated number of carbon atomsattached through a sulphur bridge; for example trifluoromethyl-S-, andpentafluoroethyl-S-. The term “polyhaloalkyloxy” as used herein refersto an “alkoxy” or “alkyloxy” group as defined above which includes from2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl,preferably F, such as polyfluoroalkoxy, for example, CF₃CH₂O, CF₃O orCF₃CF₂CH₂O.

“Hydroxyalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more hydroxyl (OH). “C₁ to C₆hydroxyalkyl” (or hydroxyalkyl), is intended to include C₁, C₂, C₃, C₄,C₅, and C₆ hydroxyalkyl groups.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. “C₃ to C₈ cycloalkyl” or “C₃₋₈cycloalkyl” is intended to include C₃, C₄, C₅, C₆, C₇, and C₈ cycloalkylgroups, including monocyclic, bicyclic, and polycyclic rings. Examplecycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkylgroups such as 1-methylcyclopropyl and 2-methylcyclopropyl and spiro andbridged cycloalkyl groups are included in the definition of“cycloalkyl”.

The term “cycloheteroalkyl” refers to cyclized heteroalkyl groups,including mono-, bi- or poly-cyclic ring systems. “C₃ to C₇cycloheteroalkyl” or “C₃₋₇ cycloheteroalkyl” is intended to include C₃,C₄, C₅, C₆, and C₇ cycloheteroalkyl groups. Example cycloheteroalkylgroups include, but are not limited to, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,and piperazinyl. Branched cycloheteroalkyl groups, such aspiperidinylmethyl, piperazinylmethyl, morpholinylmethyl,pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, and pyrazinylmethyl,are included in the definition of “cycloheteroalkyl”.

As used herein, “carbocycle”, “carbocyclyl” or “carbocyclic residue” isintended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclicor bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic ortricyclic hydrocarbon ring, any of which may be saturated, partiallyunsaturated, unsaturated or aromatic. Examples of such carbocyclesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl,cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shownabove, bridged rings are also included in the definition of carbocycle(e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,and indanyl. When the term “carbocyclyl” is used, it is intended toinclude “aryl”. A bridged ring occurs when one or more carbon atoms linktwo non-adjacent carbon atoms. Preferred bridges are one or two carbonatoms. It is noted that a bridge always converts a monocyclic ring intoa tricyclic ring. When a ring is bridged, the substituents recited forthe ring may also be present on the bridge.

Furthermore, the term “carbocyclyl”, including “cycloalkyl” and“cycloalkenyl”, as employed herein alone or as part of another groupincludes saturated or partially unsaturated (containing 1 or 2 doublebonds) cyclic hydrocarbon groups containing 1 to 3 rings, includingmonocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of3 to 20 carbons forming the rings, preferably 3 to 10 carbons or 3 to 6carbons, forming the ring and which may be fused to 1 or 2 aromaticrings as described for aryl, which include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl andcyclododecyl, cyclohexenyl,

any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, nitro, cyano, thiol and/or alkylthio and/or any ofthe alkyl substituents.

As used herein, the term “bicyclic carbocyclyl” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

As used herein, the term “aryl”, as employed herein alone or as part ofanother group, refers to monocyclic or polycyclic (including bicyclicand tricyclic) aromatic hydrocarbons, including, for example, phenyl,naphthyl, anthracenyl, and phenanthranyl. Aryl moieties are well knownand described, for example, in Lewis, R.J., ed., Hawley’s CondensedChemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York(1997). In one embodiment, the term “aryl” denotes monocyclic andbicyclic aromatic groups containing 6 to 10 carbons in the ring portion(such as phenyl or naphthyl including 1-naphthyl and 2-naphthyl). Forexample, “C₆ or C₁₀ aryl” or “C₆₋₁₀ aryl” refers to phenyl and naphthyl.Unless otherwise specified, “aryl”, “C₆ or C₁₀ aryl”, “C₆₋₁₀ aryl”, or“aromatic residue” may be unsubstituted or substituted with 1 to 5groups, preferably 1 to 3 groups, selected from —OH, —OCH₃, —Cl, —F,—Br, —I, —CN, —NO₂, —NH₂, —N(CH₃)H, —N(CH₃)₂, —CF₃, —OCF₃, —C(O)CH₃,—SCH₃, —S(O)CH₃, —S(O)₂CH_(3,) —CH₃, —CH₂CH₃, —CO₂H, and —CO₂CH₃.

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group, wherein said phenylgroup may optionally be substituted with 1 to 5 groups, preferably 1 to3 groups, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃,OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, andCO₂CH₃.

As used herein, the term “heterocycle”, “heterocyclyl”, or “heterocyclicgroup” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-memberedpolycyclic (including bicyclic and tricyclic) heterocyclic ring that issaturated, or partially unsaturated, and that contains carbon atoms and1, 2, 3 or 4 heteroatoms independently selected from N, O and S; andincluding any polycyclic group in which any of the above-definedheterocyclic rings is fused to a carbocyclic or an aryl (e.g., benzene)ring. That is, the term “heterocycle”, “heterocyclyl”, or “heterocyclicgroup” includes non-aromatic ring systems, such as heterocycloalkyl andheterocycloalkenyl. The nitrogen and sulfur heteroatoms may optionallybe oxidized (i.e., N→O and S(O)_(p), wherein p is 0, 1 or 2). Thenitrogen atom may be substituted or unsubstituted (i.e., N or NR whereinR is H or another substituent, if defined). The heterocyclic ring may beattached to its pendant group at any heteroatom or carbon atom thatresults in a stable structure. The heterocyclic rings described hereinmay be substituted on carbon or on a nitrogen atom if the resultingcompound is stable. A nitrogen in the heterocycle may optionally bequaternized. It is preferred that when the total number of S and O atomsin the heterocycle exceeds 1, then these heteroatoms are not adjacent toone another. It is preferred that the total number of S and O atoms inthe heterocycle is not more than 1. Examples of hetercyclyl include,without limitation, azetidinyl, piperazinyl, piperidinyl, piperidonyl,piperonyl, pyranyl, morpholinyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, morpholinyl,dihydrofuro[2,3-b]tetrahydrofuran.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromN, O and S. Of the two fused rings, one ring is a 5- or 6-memberedmonocyclic aromatic ring comprising a 5-membered heteroaryl ring, a6-membered heteroaryl ring or a benzo ring, each fused to a second ring.The second ring is a 5- or 6-membered monocyclic ring which issaturated, partially unsaturated, or unsaturated, and comprises a5-membered heterocycle, a 6-membered heterocycle or a carbocycle(provided the first ring is not benzo when the second ring is acarbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1. Examples of a bicyclic heterocyclic group are, but notlimited to, 1,2,3,4-tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl,2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl,and 1,2,3,4-tetrahydro-quinazolinyl.

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more atoms (i.e., C, O, N, or S) linktwo non-adjacent carbon or nitrogen atoms. Examples of bridged ringsinclude, but are not limited to, one carbon atom, two carbon atoms, onenitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It isnoted that a bridge always converts a monocyclic ring into a tricyclicring. When a ring is bridged, the substituents recited for the ring mayalso be present on the bridge.

As used herein, the term “heteroaryl” is intended to mean stablemonocyclic and polycyclic (including bicyclic and tricyclic) aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Examples of heteroaryl also include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,1H-indazolyl, imidazolopyridinyl, indolenyl, indolinyl, indolizinyl,indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl,oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathianyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl,pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl,pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl.

Examples of 5- to 10-membered heteroaryl include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrazolyl, imidazolyl, imidazolidinyl,indolyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl,thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl,benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl,benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl,benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl,isoquinolinyl, octahydroisoquinolinyl, isoxazolopyridinyl, quinazolinyl,quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl,imidazolopyridinyl, and pyrazolopyridinyl. Examples of 5- to 6-memberedheteroaryl include, but are not limited to, pyridinyl, furanyl, thienyl,pyrrolyl, pyrazolyl, pyrazinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl,thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl. In someembodiments, the heteroaryl are selected from benzthiazolyl,imidazolpyridinyl, pyrrolopyridinyl, quinolinyl, and indolyl.

Unless otherwise indicated, “carbocyclyl” or “heterocyclyl” includes oneto three additional rings fused to the carbocyclic ring or theheterocyclic ring (such as aryl, cycloalkyl, heteroaryl orcycloheteroalkyl rings), for example,

and may be optionally substituted through available carbon or nitrogenatoms (as applicable) with 1, 2, or 3 groups selected from hydrogen,halo, haloalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, alkenyl,trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl-alkyl,cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl,aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl,arylalkenyl, aminocarbonylaryl, arylthio, arylsulfinyl, arylazo,heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy,hydroxy, nitro, cyano, thiol, alkylthio, arylthio, heteroarylthio,arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl,alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl,alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylaminoand arylsulfonaminocarbonyl and/or any of the alkyl substituents set outherein.

When any of the terms alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl are used as part of another group,the number of carbon atoms and ring members are the same as thosedefined in the terms by themselves. For example, alkoxy, haloalkoxy,alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxy,alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino,alkylthio, and the like each independently contains the number of carbonatoms which are the same as defined for the term “alkyl”, such as 1 to 4carbon atoms, 1 to 6 carbon atoms, 1 to 10 carbon atoms, etc. Similarly,cycloalkoxy, heterocyclyloxy, cycloalkylamino, heterocyclylamino,aralkylamino, arylamino, aryloxy, aralkyloxy, heteroaryloxy,heteroarylalkyloxy, and the like each indepdently contains ring memberswhich are the same as defined for the terms “cycloalkyl”,“heterocyclyl”, “aryl”, and “heteroaryl”, such as 3 to 6-membered, 4 to7-membered, 6 to 10-membered, 5 to 10-membered, 5 or 6-membered, etc.

In accordance with a convention used in the art, a bond pointing to abold line, such as

as used in structural formulas herein, depicts the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

In accordance with a convention used in the art, a wavy or squiggly bondin a structural formula, such as

is used to depict a stereogenic center of the carbon atom to which X′,Y′, and Z′ are attached and is intended to represent both enantiomers ina single figure. That is, a structural formula with such as wavy bonddenotes each ofthe enantiomers individually, such as

as well as a racemic mixture thereof. When a wavy or squiggly bond isattached to a double bond (such as C═C or C=N) moiety, it include cis-or trans- (or E- and Z-) geometric isomers or a mixture thereof.

It is understood herein that if a carbocyclic or heterocyclic moiety maybe bonded or otherwise attached to a designated substrate throughdiffering ring atoms without denoting a specific point of attachment,then all possible points are intended, whether through a carbon atom or,for example, a trivalent nitrogen atom. For example, the term “pyridyl”means 2-, 3- or 4-pyridyl, the term “thienyl” means 2- or 3-thienyl, andso forth.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

One skilled in the art will recognize that substituents and othermoieties of the compounds of the present invention should be selected inorder to provide a compound which is sufficiently stable to provide apharmaceutically useful compound which can be formulated into anacceptably stable pharmaceutical composition. Compounds of the presentinvention which have such stability are contemplated as falling withinthe scope of the present invention.

The term “counter ion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate. The term“metal ion” refers to alkali metal ions such as sodium, potassium orlithium and alkaline earth metal ions such as magnesium and calcium, aswell as zinc and aluminum.

As referred to herein, the term “substituted” means that at least onehydrogen atom (attached to carbon atom or heteroatom) is replaced with anon-hydrogen group, provided that normal valencies are maintained andthat the substitution results in a stable compound. When a substituentis oxo (i.e., =O), then 2 hydrogens on the atom are replaced. Oxosubstituents are not present on aromatic moieties. When a ring system(e.g., carbocyclic or heterocyclic) is said to be substituted with acarbonyl group or a double bond, it is intended that the carbonyl groupor double bond be part (i.e., within) of the ring. Ring double bonds, asused herein, are double bonds that are formed between two adjacent ringatoms (e.g., C═C, C═N, or N═N). The term “substituted” in reference toalkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkylene, aryl,arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, and heterocyclyl,means alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, alkylene, aryl,arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, and heterocyclyl,respectively, in which one or more hydrogen atoms, which are attached toeither carbon or heteroatom, are each independently replaced with one ormore non-hydrogen substituent(s).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0, 1, 2, or 3 R groups, then saidgroup be unsubstituted when it is substituted with 0 R group, or besubstituted with up to three R groups, and at each occurrence R isselected independently from the definition of R.

Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

As used herein, the term “tautomer” refers to each of two or moreisomers of a compound that exist together in equilibrium, and arereadily interchanged by migration of an atom or group within themolecule For example, one skilled in the art would readily understandthat a 1,2,3-triazole exists in two tautomeric forms as defined above:

Thus, this disclosure is intended to cover all possible tautomers evenwhen a structure depicts only one of them.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The compounds of the present invention can be present as salts, whichare also within the scope of this invention. Pharmaceutically acceptablesalts are preferred. As used herein, “pharmaceutically acceptable salts”refer to derivatives of the disclosed compounds wherein the parentcompound is modified by making acid or base salts thereof. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington’sPharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton,PA (1990), the disclosure of which is hereby incorporated by reference.

If the compounds of the present invention have, for example, at leastone basic center, they can form acid addition salts. These are formed,for example, with strong inorganic acids, such as mineral acids, forexample sulfuric acid, phosphoric acid or a hydrohalic acid, withorganic carboxylic acids, such as alkanecarboxylic acids of 1 to 4carbon atoms, for example acetic acid, which are unsubstituted orsubstituted, for example, by halogen as chloroacetic acid, such assaturated or unsaturated dicarboxylic acids, for example oxalic,malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, suchas hydroxycarboxylic acids, for example ascorbic, glycolic, lactic,malic, tartaric or citric acid, such as amino acids, (for exampleaspartic or glutamic acid or lysine or arginine), or benzoic acid, orwith organic sulfonic acids, such as (C₁-C₄) alkyl or arylsulfonic acidswhich are unsubstituted or substituted, for example by halogen, forexample methyl- or p-toluene- sulfonic acid. Corresponding acid additionsalts can also be formed having, if desired, an additionally presentbasic center. The compounds of the present invention having at least oneacid group (for example COOH) can also form salts with bases. Suitablesalts with bases are, for example, metal salts, such as alkali metal oralkaline earth metal salts, for example sodium, potassium or magnesiumsalts, or salts with ammonia or an organic amine, such as morpholine,thiomorpholine, piperidine, pyrrolidine, a mono, di or tri-loweralkylamine, for example ethyl, tert-butyl, diethyl, diisopropyl,triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxylower alkylamine, for example mono, di or triethanolamine. Correspondinginternal salts may furthermore be formed. Salts which are unsuitable forpharmaceutical uses but which can be employed, for example, for theisolation or purification of free compounds of Formula (I) or theirpharmaceutically acceptable salts, are also included.

Preferred salts of the compounds of Formula (I) which contain a basicgroup include monohydrochloride, hydrogensulfate, methanesulfonate,phosphate, nitrate or acetate.

Preferred salts of the compounds of Formula (I) which contain an acidgroup include sodium, potassium and magnesium salts and pharmaceuticallyacceptable organic amines.

In addition, compounds of Formula (I) may have prodrug forms. Anycompound that will be converted in vivo to provide the bioactive agent(i.e., a compound of formula I) is a prodrug within the scope and spiritof the invention. Various forms of prodrugs are well known in the art.For examples of such prodrug derivatives, see:

-   a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and    Widder, K. et al., eds., Methods in Enzymology, 112:309-396,    Academic Press (1985);-   b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”, A    Textbook of Drug Design and Development, pp. 113-191,    Krosgaard-Larsen, P. et al., eds., Harwood Academic Publishers    (1991);-   c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);-   d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and-   e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

The compounds of the present invention contain a carboxy group which canform physiologically hydrolyzable esters that serve as prodrugs, i.e.,“prodrug esters”, by being hydrolyzed in the body to yield the compoundsof the present invention per se. Examples of physiologicallyhydrolyzable esters of compounds of the present invention include C₁ toC₆ alkyl, C₁ to C₆ alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆ alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl), C₁ to C₆ alkoxycarbonyloxy-C₁to C₆ alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl,glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art. The “prodrug esters” can be formed byreacting the carboxylic acid moiety of the compounds of the presentinvention with either alkyl or aryl alcohol, halide, or sulfonateemploying procedures known to those skilled in the art. Such esters maybe prepared by conventional techniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F.D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al.,Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry andEnzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth,C.G., ed., The Practice of Medicinal Chemistry, Academic Press, SanDiego, CA (1999).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Deuterium has one proton and one neutron in its nucleus andthat has twice the mass of ordinary hydrogen. Deuterium can berepresented by symbols such as “²H” or “D”. The term “deuterated”herein, by itself or used to modify a compound or group, refers toreplacement of one or more hydrogen atom(s), which is attached tocarbon(s), with a deuterium atom. Isotopes of carbon include ¹³C and¹⁴C.

Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds have a variety of potential uses,e.g., as standards and reagents in determining the ability of apotential pharmaceutical compound to bind to target proteins orreceptors, or for imaging compounds of this invention bound tobiological receptors in vivo or in vitro.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for example,when one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations

Abbreviations as used herein, are defined as follows: “1 x” for once, “2x” for twice, “3 x” for thrice, “ °C” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“µL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “RBF”for round bottom flask, “atm” for atmosphere, “psi” for pounds persquare inch, “conc.” for concentrate, “RCM” for ring-closing metathesis,“sat” or “sat’d ” for saturated, “SFC” for supercritical fluidchromatography “MW” for molecular weight, “mp” for melting point, “ee”for enantiomeric excess, “MS” or “Mass Spec” for mass spectrometry,“ESI” for electrospray ionization mass spectroscopy, “HR” for highresolution, “HRMS” for high resolution mass spectrometry, “LCMS” forliquid chromatography mass spectrometry, “HPLC” for high pressure liquidchromatography, “RP HPLC” for reverse phase HPLC, “TLC” or “tlc” forthin layer chromatography, “NMR” for nuclear magnetic resonancespectroscopy, “nOe” for nuclear Overhauser effect spectroscopy, “¹H” forproton, “δ” for delta, “s” for singlet, “d” for doublet, “t” fortriplet, “q” for quartet, “m” for multiplet, “br” for broad, “Hz” forhertz, and “α”, “β”, “γ”, “R”, “S”, “E”, and “Z” are stereochemicaldesignations familiar to one skilled in the art.

Me methyl Et ethyl Pr propyl i-Pr isopropyl Bu butyl i-Bu isobutyl t-Butert-butyl Ph phenyl Bn benzyl Boc or BOC tert-butyloxycarbonyl Boc₂Odi-tert-butyl dicarbonate AcOH or HOAc acetic acid AlCl₃ aluminumtrichloride AIBN Azobis-isobutyronitrile BBr₃ boron tribromide BCl₃boron trichloride BEMP2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorineBOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate Burgess reagent1-methoxy-N-triethylammoniosulfonyl-methanimidate CBz carbobenzyloxy DCMor CH₂Cl₂ dichloromethane CH₃CN or ACN acetonitrile CDCl₃deutero-chloroform CHCl₃ chloroform mCPBA or m-CPBAmeta-chloroperbenzoic acid Cs₂CO₃ cesium carbonate Cu(OAc)₂ copper (II)acetate Cy₂NMe N-cyclohexyl-N-methylcyclohexanamine DAST(Diethylamino)sulfur trifluoride DBU 1,8-diazabicyclo[5.4.0]undec-7-eneDCE 1,2 dichloroethane DEA diethylamine Dess-Martin1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one DIC orDIPCDI diisopropylcarbodiimide DIEA, DIPEA or Hunig’s basediisopropylethylamine DMAP 4-dimethylaminopyridine DME1,2-dimethoxyethane DMF dimethyl formamide DMSO dimethyl sulfoxide cDNAcomplementary DNA Dppp (R)-(+)-1,2-bis(diphenylphosphino)propane DuPhos(+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene EDCN-(3-dimthylaminopropyl)-N′-ethylcarbodiimide EDCIN-(3-dimthylaminopropyl)-N′-ethylcarbodiimide hydrochloride EDTAethylenediaminetetraacetic acid (S,S)-EtDuPhosRh(I)(+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rhodium(I)trifluoromethanesulfonate Et₃N or TEA triethylamine EtOAc ethyl acetateEt₂O diethyl ether EtOH ethanol GMF glass microfiber filter Grubbs II(1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(triycyclohexylphosphine)ruthenium HCl hydrochloricacid HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate HEPES 4-(2-hydroxyethyl)piperaxine-1-ethanesulfonicacid Hex hexane HOBt or HOBT 1-hydroxybenzotriazole H₂O₂ hydrogenperoxide IBX 2-iodoxybenzoic acid H₂SO₄ sulfuric acid Jones reagent CrO₃in aqueous H₂SO₄, 2 M solution K₂CO₃ potassium carbonate K₂HPO₄potassium phosphate dibasic (potassium hydrogen phosphate) KOAcpotassium acetate K₃PO₄ potassium phosphate tribasic LAH lithiumaluminum hydride LDA lithium diisopropylamide LG leaving group LiOHlithium hydroxide MeOH methanol MgSO₄ magnesium sulfate MsOH or MSAmethylsulfonic acid/methanesulfonic acid NaCl sodium chloride NaH sodiumhydride NaHCO₃ sodium bicarbonate Na₂CO₃ sodium carbonate NaOH sodiumhydroxide Na₂SO₃ sodium sulfite Na₂SO₄ sodium sulfate NBSN-bromosuccinimide NCS N-chlorosuccinimide NH₃ ammonia NH₄Cl ammoniumchloride NH₄OH ammonium hydroxide NH₄ ⁺HCO₂ ⁻ ammonium formate NMMN-methylmorpholine OTf triflate or trifluoromethanesulfonate Pd₂(dba)₃tris(dibenzylideneacetone)dipalladium(0) Pd(OAc)₂ palladium(II) acetatePd/C palladium on carbon Pd(dppf)Cl₂[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) Ph₃PCl₂triphenylphosphine dichloride PG protecting group POCl₃ phosphorusoxychloride PPTS pyridinium p-toluenesulfonate i-PrOH or IPA isopropanolPS Polystyrene RT or rt room temperature SEM-Cl2-(trimethysilyl)ethoxymethyl chloride SiO₂ silica oxide SnCl₂ tin(II)chloride TBAF tetra-n-butylammonium fluoride TBAI tetra-n-butylammoniumiodide TFA trifluoroacetic acid THF tetrahydrofuran THP tetrahydropyranTMSCHN₂ Trimethylsilyldiazomethane TMSCH₂N₃ Trimethylsilylmethyl azideT3P propane phosphonic acid anhydride TRIS tris (hydroxymethyl)aminomethane pTsOH p-toluenesulfonic acid

IV. Biology

Lysophospholipids are membrane-derived bioactive lipid mediators.Lysophospholipids include, but are not limited to, lysophosphatidic acid(1-acyl-2-hydroxy-sn-glycero-3-phosphate; LPA), sphingosine 1-phosphate(S1P), lysophosphatidylcholine (LPC), and sphingosylphosphorylcholine(SPC). Lysophospholipids affect fundamental cellular functions thatinclude cellular proliferation, differentiation, survival, migration,adhesion, invasion, and morphogenesis. These functions influence manybiological processes that include neurogenesis, angiogenesis, woundhealing, immunity, and carcinogenesis.

LPA acts through sets of specific G protein-coupled receptors (GPCRs) inan autocrine and paracrine fashion. LPA binding to its cognate GPCRs(LPA₁, LPA₂, LPA₃, LPA₄, LPA₅, LPA₆) activates intracellular signalingpathways to produce a variety of biological responses.

Lysophospholipids, such as LPA, are quantitatively minor lipid speciescompared to their major phospholipid counterparts (e.g.,phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin). LPAhas a role as a biological effector molecule, and has a diverse range ofphysiological actions such as, but not limited to, effects on bloodpressure, platelet activation, and smooth muscle contraction, and avariety of cellular effects, which include cell growth, cell rounding,neurite retraction, and actin stress fiber formation and cell migration.The effects of LPA are predominantly receptor mediated.

Activation of the LPA receptors (LPA₁, LPA₂, LPA₃, LPA₄, LPA₅, LPA₆)with LPA mediates a range of downstream signaling cascades. Theseinclude, but are not limited to, mitogen-activated protein kinase (MAPK)activation, adenylyl cyclase (AC) inhibition/activation, phospholipase C(PLC) activation/Ca²⁺ mobilization, arachidonic acid release, Akt/PKBactivation, and the activation of small GTPases, Rho, ROCK, Rac, andRas. Other pathways that are affected by LPA receptor activationinclude, but are not limited to, cyclic adenosine monophosphate (cAMP),cell division cycle 42/GTP-binding protein (Cdc42), proto-oncogeneserine/threonine-protein kinase Raf (c-RAF), proto-oncogenetyrosine-protein kinase Src (c-src), extracellular signal-regulatedkinase (ERK), focal adhesion kinase (FAK), guanine nucleotide exchangefactor (GEF), glycogen synthase kinase 3b (GSK3b), c-jun amino-terminalkinase (JNK), MEK, myosin light chain II (MLC II), nuclear factor kB(NF-kB), N-methyl-D-aspartate (NMDA) receptor activation,phosphatidylinositol 3-kinase (PI3K), protein kinase A (PKA), proteinkinase C (PKC), ras-related C3 botulinum toxin substrate 1 (RAC1). Theactual pathway and realized end point are dependent on a range ofvariables that include receptor usage, cell type, expression level of areceptor or signaling protein, and LPA concentration. Nearly allmammalian cells, tissues and organs co-express several LPA-receptorsubtypes, which indicates that LPA receptors signal in a cooperativemanner. LPA₁, LPA₂, and LPA₃ share high amino acid sequence similarity.

LPA is produced from activated platelets, activated adipocytes, neuronalcells, and other cell types. Serum LPA is produced by multiple enzymaticpathways that involve monoacylglycerol kinase, phospholipase A₁,secretory phospholipase A₂, and lysophospholipase D (lysoPLD), includingautotaxin. Several enzymes are involved in LPA degradation:lysophospholipase, lipid phosphate phosphatase, and LPA acyl transferasesuch as endophilin. LPA concentrations in human serum are estimated tobe 1-5 µM. Serum LPA is bound to albumin, low-density lipoproteins, orother proteins, which possibly protect LPA from rapid degradation. LPAmolecular species with different acyl chain lengths and saturation arenaturally occurring, including 1-palmitoyl (16:0), 1-palmitoleoyl(16:1), 1-stearoyl (18:0), 1-oleoyl (18:1), 1-linoleoyl (18:2), and1-arachidonyl (20:4) LPA. Quantitatively minor alkyl LPA has biologicalactivities similar to acyl LPA, and different LPA species activate LPAreceptor subtypes with varied efficacies.

LPA Receptors

LPA₁ (previously called VZG-1/EDG-2/mrec1.3) couples with three types ofG proteins, G_(i/o), G_(q), and G_(12/13). Through activation of these Gproteins, LPA induces a range of cellular responses through LPA₁including but not limited to: cell proliferation, serum-response element(SRE) activation, mitogen-activated protein kinase (MAPK) activation,adenylyl cyclase (AC) inhibition, phospholipase C (PLC) activation, Ca²⁺mobilization, Akt activation, and Rho activation.

Wide expression of LPA₁ is observed in adult mice, with clear presencein testis, brain, heart, lung, small intestine, stomach, spleen, thymus,and skeletal muscle. Similarly, human tissues also express LPA₁; it ispresent in brain, heart, lung, placenta, colon, small intestine,prostate, testis, ovary, pancreas, spleen, kidney, skeletal muscle, andthymus.

LPA₂ (EDG-4) also couples with three types of G proteins, G_(i/o),G_(q), and G_(12/13), to mediate LPA-induced cellular signaling.Expression of LPA₂ is observed in the testis, kidney, lung, thymus,spleen, and stomach of adult mice and in the human testis, pancreas,prostate, thymus, spleen, and peripheral blood leukocytes. Expression ofLPA₂ is upregulated in various cancer cell lines, and several human LPA₂transcriptional variants with mutations in the 3′-untranslated regionhave been observed. Targeted deletion of LPA₂ in mice has not shown anyobvious phenotypic abnormalities, but has demonstrated a significantloss of normal LPA signaling (e.g., PLC activation, Ca²⁺ mobilization,and stress fiber formation) in primary cultures of mouse embryonicfibroblasts (MEFs). Creation of lpa1(-/-) lpa2 (-/-) double-null micehas revealed that many LPA-induced responses, which include cellproliferation, AC inhibition, PLC activation, Ca²⁺ mobilization, JNK andAkt activation, and stress fiber formation, are absent or severelyreduced in double-null MEFs. All these responses, except for ACinhibition (AC inhibition is nearly abolished in LPA₁ (-/-) MEFs), areonly partially affected in either LPA₁ (-/-) or LPA₂ (-/-) MEFs. LPA₂contributes to normal LPA-mediated signaling responses in at least somecell types (Choi et al, Biochemica et Biophysica Acta 2008, 1781,p531-539).

LPA₃ (EDG-7) is distinct from LPA₁ and LPA₂ in its ability to couplewith G_(i/o) and G_(q) but not G_(12/13) and is much less responsive toLPA species with saturated acyl chains. LPA₃ can mediate pleiotropicLPA-induced signaling that includes PLC activation, Ca²⁺ mobilization,AC inhibition/activation, and MAPK activation. Overexpression of LPA₃ inneuroblastoma cells leads to neurite elongation, whereas that of LPA₁ orLPA₂ results in neurite retraction and cell rounding when stimulatedwith LPA. Expression of LPA₃ is observed in adult mouse testis, kidney,lung, small intestine, heart, thymus, and brain. In humans, it is foundin the heart, pancreas, prostate, testis, lung, ovary, and brain(frontal cortex, hippocampus, and amygdala).

LPA₄ (p2y₉/GPR23) is of divergent sequence compared to LPA₁, LPA₂, andLPA₃ with closer similarity to the platelet-activating factor (PAF)receptor. LPA₄ mediates LPA induced Ca²⁺ mobilization and cAMPaccumulation, and functional coupling to the G protein Gs for ACactivation, as well as coupling to other G proteins. The LPA₄ gene isexpressed in the ovary, pancreas, thymus, kidney and skeletal muscle.

LPA₅ (GPR92) is a member of the purinocluster of GPCRs and isstructurally most closely related to LPA₄. LPA₅ is expressed in humanheart, placenta, spleen, brain, lung and gut. LPA₅ also shows very highexpression in the CD8+ lymphocyte compartment of the gastrointestinaltract.

LPA₆ (p2y5) is a member of the purinocluster of GPCRs and isstructurally most closely related to LPA₄. LPA₆ is an LPA receptorcoupled to the G12/13-Rho signaling pathways and is expressed in theinner root sheaths of human hair follicles.

Illustrative Biological Activity Wound Healing

Normal wound healing occurs by a highly coordinated sequence of eventsin which cellular, soluble factors and matrix components act in concertto repair the injury. The healing response can be described as takingplace in four broad, overlapping phases-hemostasis, inflammation,proliferation, and remodeling. Many growth factors and cytokines arereleased into a wound site to initiate and perpetuate wound healingprocesses.

When wounded, damaged blood vessels activate platelets. The activatedplatelets play pivotal roles in subsequent repair processes by releasingbioactive mediators to induce cell proliferation, cell migration, bloodcoagulation, and angiogenesis. LPA is one such mediator that is releasedfrom activated platelets; this induces platelet aggregation along withmitogenic/migration effects on the surrounding cells, such asendothelial cells, smooth muscle cells, fibroblasts, and keratinocytes.

Topical application of LPA to cutaneous wounds in mice promotes repairprocesses (wound closure and increased neoepithelial thickness) byincreasing cell proliferation/ migration without affecting secondaryinflammation.

Activation of dermal fibroblasts by growth factors and cytokines leadsto their subsequent migration from the edges of the wound into theprovisional matrix formed by the fibrin clot whereupon the fibroblastsproliferate and start to restore the dermis by secreting and organizingthe characteristic dermal extracellular matrix (ECM). The increasingnumber of fibroblasts within the wound and continuous precipitation ofECM enhances matrix rigidity by applying small tractional forces to thenewly formed granulation tissue. The increase in mechanical stress, inconjunction with transforming growth factor β (TGFβ), induces α-smoothmuscle actin (α-SMA) expression and the subsequent transformation offibroblasts into myofibroblasts. Myofibroblasts facilitate granulationtissue remodeling via myofibroblast contraction and through theproduction of ECM components.

LPA regulates many important functions of fibroblasts in wound healing,including proliferation, migration, differentiation and contraction.Fibroblast proliferation is required in wound healing in order to fillan open wound. In contrast, fibrosis is characterized by intenseproliferation and accumulation of myofibroblasts that activelysynthesize ECM and proinflammatory cytokines. LPA can either increase orsuppress the proliferation of cell types important in wound healing,such as epithelial and endothelial cells (EC),macrophages,keratinocytes, and fibroblasts. A role for LPA₁ in LPA-inducedproliferation was provided by the observation that LPA-stimulatedproliferation of fibroblasts isolated from LPA₁ receptor null mice wasattenuated (Mills et al, Nat Rev. Cancer 2003; 3: 582-591). LPA inducescytoskeletal changes that are integral to fibroblast adhesion,migration, differentiation and contraction.

Fibrosis

Tissue injury initiates a complex series of host wound-healingresponses; if successful, these responses restore normal tissuestructure and function. If not, these responses can lead to tissuefibrosis and loss of function.

For the majority of organs and tissues the development of fibrosisinvolves a multitude of events and factors. Molecules involved in thedevelopment of fibrosis include proteins or peptides (profibroticcytokines, chemokines, metalloproteinases etc.) and phospholipids.Phospholipids involved in the development of fibrosis include plateletactivating factor (PAF), phosphatidyl choline, sphingosine-1 phosphate(S1P) and lysophosphatidic acid (LPA).

A number of muscular dystrophies are characterized by a progressiveweakness and wasting of musculature, and by extensive fibrosis. It hasbeen shown that LPA treatment of cultured myoblasts induced significantexpression of connective tissue growth factor (CTGF). CTGF subsequentlyinduces collagen, fibronectin and integrin expression and inducesdedifferentiation of these myoblasts. Treatment of a variety of celltypes with LPA induces reproducible and high level induction of CTGF(J.P. Pradere, et al., LPA₁ receptor activation promotes renalinterstitial fibrosis, J. Am. Soc. Nephrol. 18 (2007) 3110-3118; N.Wiedmaier, et al., Int J Med Microbiol; 298(3-4):231-43, 2008). CTGF isa profibrotic cytokine, signaling down-stream and in parallel with TGFβ.

CTGF expression by gingival epithelial cells, which are involved in thedevelopment of gingival fibromatosis, was found to be exacerbated by LPAtreatment (A. Kantarci, et al., J. Pathol. 210 (2006) 59-66).

LPA is associated with the progression of liver fibrosis. In vitro, LPAinduces stellate cell and hepatocyte proliferation. These activatedcells are the main cell type responsible for the accumulation of ECM inthe liver. Furthermore, LPA plasma levels rise during CCl₄-induced liverfibrosis in rodents, or in hepatitis C virus-induced liver fibrosis inhumans (N. Watanabe, et al., Plasma lysophosphatidic acid level andserum autotaxin activity are increased in liver injury in rats inrelation to its severity, Life Sci. 81 (2007) 1009-1015; N.Watanabe, etal., J. Clin. Gastroenterol. 41 (2007) 616-623).

An increase of phospholipid concentrations in the bronchoalveolar lavagefluid in rabbits and rodents injected with bleomycin has been reported(K. Kuroda, et al., Phospholipid concentration in lung lavage fluid asbiomarker for pulmonary fibrosis, Inhal. Toxicol. 18 (2006) 389-393; K.Yasuda, et al., Lung 172 (1994) 91-102).

LPA is associated with heart disease and mycocardial remodeling. SerumLPA levels are increased after myocardial infarction in patients and LPAstimulates rat cardiac fibroblast proliferation and collagen production(Chen et al. FEBS Lett. 2006 Aug 21;580(19):4737-45).

Pulmonary Fibrosis

In the lung, aberrant wound healing responses to injury contribute tothe pathogenesis of fibrotic lung diseases. Fibrotic lung diseases, suchas idiopathic pulmonary fibrosis (IPF), are associated with highmorbidity and mortality.

LPA is an important mediator of fibroblast recruitment in pulmonaryfibrosis. LPA and LPA₁ play key pathogenic roles in pulmonary fibrosis.Fibroblast chemoattractant activity plays an important role in the lungsin patients with pulmonary fibrosis. Profibrotic effects ofLPA₁-receptor stimulation is explained by LPA₁-receptor-mediatedvascular leakage and increased fibroblast recruitment, both profibroticevents. The LPA-LPA₁ pathway has a role in mediating fibroblastmigration and vascular leakage in IPF. The end result is the aberranthealing process that characterizes this fibrotic condition.

The LPA₁ receptor is the LPA receptor most highly expressed onfibroblasts obtained from patients with IPF. Furthermore, BAL obtainedfrom IPF patients induced chemotaxis of human foetal lung fibroblaststhat was blocked by the dual LPA₁- LPA₃ receptor antagonist Ki16425. Inan experimental bleomycin-induced lung injury mouse model, it was shownthat LPA levels were high in bronchoalveolar lavage samples comparedwith unexposed controls. LPA₁ knockout mice are protected from fibrosisafter bleomycin challenge with reduced fibroblast accumulation andvascular leakage. In human subjects with IPF, high LPA levels wereobserved in bronchoalveolar lavage samples compared with healthycontrols. Increased fibroblast chemotactic activity in these samples wasinhibited by the Ki 16425 indicating that fibroblast migration ismediated by the LPA-LPA receptor(s) pathway (Tager et al. NatureMedicine, 2008, 14, 45-54).

The LPA-LPA₁ pathway is crucial in fibroblast recruitment and vascularleakage in pulmonary fibrosis.

Activation of latent TGF-β by the αvβ6 integrin plays a critical role inthe development of lung injury and fibrosis (Munger et al. Cell, vol.96, 319-328, 1999). LPA induces αvβ6-mediated TGF-β activation on humanlung epithelial cells (Xu et al. Am. J. Pathology, 2009, 174,1264-1279). The LPA-induced αvβ6-mediated TGF-β activation is mediatedby the LPA₂ receptor. Expression of the LPA₂ receptor is increased inepithelial cells and mesenchymal cells in areas of lung fibrosis fromIPF patients compared to normal human lung tissue. The LPA-LPA₂ pathwaycontributes to the activation of the TGF-β pathway in pulmonaryfibrosis. In some embodiments, compounds that inhibit LPA₂ show efficacyin the treatment of lung fibrosis. In some embodiments, compounds thatinhibit both LPA₁ and LPA₂ show improved efficacy in the treatment oflung fibrosis compared to compounds which inhibit only LPA₁ or LPA₂.

The LPA₁ antagonist BMS-986020 was shown to significantly reduce therate of FVC (forced vital capacity) decline in a 26-week clinical trialin IPF patients (Palmer et al., Chest, 2018, 154, 1061-1069).

Renal Fibrosis

LPA and LPA₁ are involved in the etiology of kidney fibrosis. LPA haseffects on both proliferation and contraction of glomerular mesangialcells and thus has been implicated in proliferative glomerulonephritis(C.N. Inoue, et al., Clin. Sci. (Colch.) 1999, 96, 431-436). In ananimal model of renal fibrosis [unilateral ureteral obstruction (UUO)],it was found that renal LPA receptors are expressed under basalconditions with an expression order of LPA₂>LPA₃=LPA₁>>LPA₄. This modelmimics in an accelerated manner the development of renal fibrosisincluding renal inflammation, fibroblast activation and accumulation ofextracellular matrix in the tubulointerstitium. UUO significantlyinduced LPA₁-receptor expression. This was paralleled by renal LPAproduction (3.3 fold increase) in conditioned media from kidneyexplants. Contra-lateral kidneys exhibited no significant changes in LPArelease and LPA-receptors expression. This shows that a prerequisite foran action of LPA in fibrosis is met: production of a ligand (LPA) andinduction of one of its receptors (the LPA₁ receptor) (J.P. Pradere etal., Biochimica et Biophysica Acta, 2008, 1781, 582-587).

In mice where the LPA₁ receptor was knocked out (LPA₁ (-/-), thedevelopment of renal fibrosis was significantly attenuated. UUO micetreated with the LPA receptor antagonist Ki 16425 closely resembled theprofile of LPA₁ (-/-) mice.

LPA can participate in intraperitonial accumulation ofmonocyte/macrophages and LPA can induce expression of the profibroticcytokine CTGF in primary cultures of human fibroblasts (J.S. Koh,et al.,J. Clin. Invest., 1998, 102, 716-727).

LPA treatment of a mouse epithelial renal cell line, MCT, induced arapid increase in the expression of the profibrotic cytokine CTGF. CTGFplays a crucial role in UUO-induced tubulointerstitial fibrosis (TIF),and is involved in the profibrotic activity of TGFβ. This induction wasalmost completely suppressed by co-treatment with the LPA-receptorantagonist Ki 16425. In one aspect, the profibrotic activity of LPA inkidney results from a direct action of LPA on kidney cells involvinginduction of CTGF.

Hepatic Fibrosis

LPA is implicated in liver disease and fibrosis. Plasma LPA levels andserum autotaxin (enzyme responsible for LPA production) are elevated inhepatitis patients and animal models of liver injury in correlation withincreased fibrosis. LPA also regulates liver cell function. LPA₁ andLPA₂ receptors are expressed by mouse hepatic stellate cells and LPAstimulates migration of hepatic myofibroblasts.

Ocular Fibrosis

LPA is in involved in wound healing in the eye. LPA₁ and LPA₃ receptorsare detectable in the normal rabbit corneal epithelial cells,keratocytes and endothelial cells and LPA₁ and LPA₃ expression areincreased in corneal epithelial cells following injury.

LPA and its homologues are present in the aqueous humor and the lacrimalgland fluid of the rabbit eye and these levels are increased in a rabbitcorneal injury model.

LPA induces actin stress fiber formation in rabbit corneal endothelialand epithelial cells and promotes contraction corneal fibroblasts. LPAalso stimulates proliferation of human retinal pigmented epithelialcells

Cardiac Fibrosis

LPA is implicated in myocardial infarction and cardiac fibrosis. SerumLPA levels are increased in patients following mycocardial infarction(MI) and LPA stimulates proliferation and collagen production (fibrosis)by rat cardiac fibroblasts. Both LPA1 and LPA3 receptors are highlyexpressed in human heart tissue.

Treatment of Fibrosis

In one aspect, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is used to treat or prevent fibrosis in amammal. In one aspect, a compound of Formulas (I), or a pharmaceuticallyacceptable salt thereof, is used to treat fibrosis of an organ or tissuein a mammal. In one aspect is a method for preventing a fibrosiscondition in a mammal, the method comprising administering to the mammalat risk of developing one or more fibrosis conditions a therapeuticallyeffective amount of a compound of Formulas (I), or a pharmaceuticallyacceptable salt thereof. In one aspect, the mammal has been exposed toone or more environmental conditions that are known to increase the riskof fibrosis of an organ or tissue. In one aspect, the mammal has beenexposed to one or more environmental conditions that are known toincrease the risk of lung, liver or kidney fibrosis. In one aspect, themammal has a genetic predisposition of developing fibrosis of an organor tissue. In one aspect, a compound of Formula (I), or apharmaceutically acceptable salt thereof, is administered to a mammal toprevent or minimize scarring following injury. In one aspect, injuryincludes surgery.

The terms “fibrosis” or “fibrosing disorder,” as used herein, refers toconditions that are associated with the abnormal accumulation of cellsand/or fibronectin and/or collagen and/or increased fibroblastrecruitment and include but are not limited to fibrosis of individualorgans or tissues such as the heart, kidney, liver, joints, lung,pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletaland digestive tract.

Exemplary diseases, disorders, or conditions that involve fibrosisinclude, but are not limited to: Lung diseases associated with fibrosis,e.g., idiopathic pulmonary fibrosis, pulmonary fibrosis secondary tosystemic inflammatory disease such as rheumatoid arthritis, scleroderma,lupus, cryptogenic fibrosing alveolitis, radiation induced fibrosis,chronic obstructive pulmonary disease (COPD), scleroderma, chronicasthma, silicosis, asbestos induced pulmonary or pleural fibrosis, acutelung injury and acute respiratory distress (including bacterialpneumonia induced, trauma induced, viral pneumonia induced, ventilatorinduced, non-pulmonary sepsis induced, and aspiration induced); Chronicnephropathies associated with injury/fibrosis (kidney fibrosis), e.g.,glomerulonephritis secondary to systemic inflammatory diseases such aslupus and scleroderma, diabetes, glomerular nephritis, focal segmentalglomerular sclerosis, IgA nephropathy, hypertension, allograft andAlport; Gut fibrosis, e.g., scleroderma, and radiation induced gutfibrosis; Liver fibrosis, e.g., cirrhosis, alcohol induced liverfibrosis, nonalcoholic steatohepatitis (NASH), biliary duct injury,primary biliary cirrhosis, infection or viral induced liver fibrosis(e.g., chronic HCV infection), and autoimmune hepatitis; Head and neckfibrosis, e.g., radiation induced; Corneal scarring, e.g., LASIK(laser-assisted in situ keratomileusis), corneal transplant, andtrabeculectomy; Hypertrophic scarring and keloids, e.g., burn induced orsurgical; and other fibrotic diseases, e.g., sarcoidosis, scleroderma,spinal cord injury/fibrosis, myelofibrosis, vascular restenosis,atherosclerosis, arteriosclerosis, Wegener’s granulomatosis, mixedconnective tissue disease, and Peyronie’s disease.

In one aspect, a mammal suffering from one of the following non-limitingexemplary diseases, disorders, or conditions will benefit from therapywith a compound of Formula (I), or a pharmaceutically acceptable saltthereof: atherosclerosis, thrombosis, heart disease, vasculitis,formation of scar tissue, restenosis, phlebitis, COPD (chronicobstructive pulmonary disease), pulmonary hypertension, pulmonaryfibrosis, pulmonary inflammation, bowel adhesions, bladder fibrosis andcystitis, fibrosis of the nasal passages, sinusitis, inflammationmediated by neutrophils, and fibrosis mediated by fibroblasts.

In one aspect, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered to a mammal with fibrosis of anorgan or tissue or with a predisposition of developing fibrosis of anorgan or tissue with one or more other agents that are used to treatfibrosis. In one aspect, the one or more agents include corticosteroids.In one aspect, the one or more agents include immunosuppressants. In oneaspect, the one or more agents include B-cell antagonists. In oneaspect, the one or more agents include uteroglobin.

In one aspect, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is used to treat a dermatological disorders ina mammal. The term “dermatological disorder,” as used herein refers to askin disorder. Such dermatological disorders include, but are notlimited to, proliferative or inflammatory disorders of the skin such as,atopic dermatitis, bullous disorders, collagenoses, psoriasis,scleroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema,urticaria, rosacea, wound healing, scarring, hypertrophic scarring,keloids, Kawasaki Disease, rosacea, Sjogren-Larsso Syndrome, urticaria.In one aspect, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is used to treat systemic sclerosis.

Pain

Since LPA is released following tissue injury, LPA₁ plays an importantrole in the initiation of neuropathic pain. LPA₁, unlike LPA₂ or LPA₃,is expressed in both dorsal root ganglion (DRG) and dorsal root neurons.Using the antisense oligodeoxynucleotide (AS-ODN) for LPA₁ and LPA₁-nullmice, it was found that LPA-induced mechanical allodynia andhyperalgesia is mediated in an LPA₁-dependent manner. LPA₁ anddownstream Rho-ROCK activation play a role in the initiation ofneuropathic pain signaling. Pretreatment with Clostridium botulinum C3exoenzyme (BoTXC3, Rho inhibitor) or Y-27632 (ROCK inhibitor) completelyabolished the allodynia and hyperalgesia in nerve-injured mice. LPA alsoinduced demyelination of the dorsal root, which was prevented by BoTXC3.The dorsal root demyelination by injury was not observed in LPA₁-nullmice or AS-ODN injected wild-type mice. LPA signaling appears to induceimportant neuropathic pain markers such as protein kinase Cγ (PKCγ) anda voltage-gated calcium channel α2δ1 subunit (Caα2δ1) in an LPA₁ andRho-dependent manner (M. Inoue, et al., Initiation of neuropathic painrequires lysophosphatidic acid receptor signaling, Nat. Med. 10 (2004)712-718).

In one aspect, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is used in the treatment of pain in a mammal.In one aspect, the pain is acute pain or chronic pain. In anotheraspect, the pain is neuropathic pain.

In one aspect, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is used in the treatment of fibromylagia. Inone aspect, fibromyalgia stems from the formation of fibrous scar tissuein contractile (voluntary) muscles. Fibrosis binds the tissue andinhibits blood flow, resulting in pain.

Cancer

Lysophospholipid receptor signaling plays a role in the etiology ofcancer. Lysophosphatidic acid (LPA) and its G protein-coupled receptors(GPCRs) LPA₁, LPA₂, and/or LPA₃ play a role in the development ofseveral types of cancers. The initiation, progression and metastasis ofcancer involve several concurrent and sequential processes includingcell proliferation and growth, survival and anti-apoptosis, migration ofcells, penetration of foreign cells into defined cellular layers and/ororgans, and promotion of angiogenesis. The control of each of theseprocesses by LPA signaling in physiological and pathophysiologicalconditions underscores the potential therapeutic usefulness ofmodulating LPA signaling pathways for the treatment of cancer,especially at the level of the LPA receptors or ATX/lysoPLD. Autotaxin(ATX) is a prometastatic enzyme initially isolated from the conditionedmedium of human melanoma cells that stimulates a myriad of biologicalactivities, including angiogenesis and the promotion of cell growth,migration, survival, and differentiation through the production of LPA(Mol Cancer Ther 2008;7(10):3352-62).

LPA signals through its own GPCRs leading to activation of multipledownstream effector pathways. Such downstream effector pathways play arole in cancer. LPA and its GPCRs are linked to cancer through majoroncogenic signaling pathways.

LPA contributes to tumorigenesis by increasing motility and invasivenessof cells. LPA has been implicated in the initiation or progression ofovarian cancer. LPA is present at significant concentrations (2-80 µM)in the ascitic fluid of ovarian cancer patients. Ovarian cancer cellsconstitutively produce increased amounts of LPA as compared to normalovarian surface epithelial cells, the precursor of ovarian epithelialcancer. Elevated LPA levels are also detected in plasma from patientswith early-stage ovarian cancers compared with controls. LPA receptors(LPA₂ and LPA₃) are also overexpressed in ovarian cancer cells ascompared to normal ovarian surface epithelial cells. LPA stimulatesCox-2 expression through transcriptional activation andpost-transcriptional enhancement of Cox-2 mRNA in ovarian cancer cells.Prostaglandins produced by Cox-2 have been implicated in a number ofhuman cancers and pharmacological inhibition of Cox-2 activity reducescolon cancer development and decreases the size and number of adenomasin patients with familial adenomatous polyposis. LPA has also beenimplicated in the initiation or progression of prostate cancer, breastcancer, melanoma, head and neck cancer, bowel cancer (colorectalcancer), thyroid cancer and other cancers (Gardell et al, Trends inMolecular Medicine, vol. 12, no. 2, p 65-75, 2006; Ishii et al, Annu.Rev. Biochem, 73, 321-354, 2004; Mills et al., Nat. Rev. Cancer, 3,582-591, 2003; Murph et al., Biochimica et Biophysica Acta, 1781,547-557, 2008).

The cellular responses to LPA are mediated through the lysophosphatidicacid receptors. For example, LPA receptors mediate both migration of andinvasion by pancreatic cancer cell lines: an antagonist of LPA₁ and LPA₃(Ki16425) and LPA₁₋ specific siRNA effectively blocked in vitromigration in response to LPA and peritoneal fluid (ascites) frompancreatic cancer patients; in addition, Ki16425 blocked the LPA-inducedand ascites-induced invasion activity of a highly peritoneal metastaticpancreatic cancer cell line (Yamada et al, J. Biol. Chem., 279,6595-6605, 2004).

Colorectal carcinoma cell lines show significant expression of LPA₁ mRNAand respond to LPA by cell migration and production of angiogenicfactors. Overexpression of LPA receptors has a role in the pathogenesisof thyroid cancer. LPA₃ was originally cloned from prostate cancercells, concordant with the ability of LPA to induce autocrineproliferation of prostate cancer cells.

LPA has stimulatory roles in cancer progression in many types of cancer.LPA is produced from and induces proliferation of prostate cancer celllines. LPA induces human colon carcinoma DLD1 cell proliferation,migration, adhesion, and secretion of angiogenic factors through LPA₁signaling. In other human colon carcinoma cells lines (HT29 and WiDR),LPA enhances cell proliferation and secretion of angiogenic factors. Inother colon cancer cell lines, LPA₂ and LPA₃ receptor activation resultsin proliferation of the cells. The genetic or pharmacologicalmanipulation of LPA metabolism, specific blockade of receptor signaling,and/or inhibition of downstream signal transduction pathways, representapproaches for cancer therapies.

It has been reported that LPA and other phospholipids stimulateexpression of interleukin-8 (IL-8) in ovarian cancer cell lines. In someembodiments, high concentrations of IL-8 in ovarian cancer correlatewith poor initial response to chemotherapy and with poor prognosis,respectively. In animal models, expression of IL-8 and other growthfactors such as vascular endothelial growth factor (VEGF) is associatedwith increased tumorigenicity, ascites formation, angiogenesis, andinvasiveness of ovarian cancer cells. In some aspects, IL-8 is animportant modulator of cancer progression, drug resistance, andprognosis in ovarian cancer. In some embodiments, a compound of Formula(I) inhibits or reduces IL-8 expression in ovarian cancer cell lines.

In one aspect, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is used in the treatment of cancer. In oneaspect, a compound of Formula (I), or a pharmaceutically acceptable saltthereof, is used in the treatment of malignant and benign proliferativedisease. In one aspect, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is used to prevent or reduce proliferation oftumor cells, invasion and metastasis of carcinomas, pleural mesothelioma(Yamada, Cancer Sci., 2008, 99(8), 1603-1610) or peritonealmesothelioma, cancer pain, bone metastases (Boucharaba et al, J. Clin.Invest., 2004, 114(12), 1714-1725; Boucharaba et al, Proc. Natl. acad.Sci., 2006, 103(25) 9643-9648). In one aspect is a method of treatingcancer in a mammal, the method comprising administering to the mammal acompound of Formula (I), or a pharmaceutically acceptable salt thereof,and a second therapeutic agent, wherein the second therapeutic agent isan anti-cancer agent.

The term “cancer,” as used herein refers to an abnormal growth of cellswhich tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). The types of cancer include, but is not limitedto, solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary,pancreas or other endocrine organ (thyroid), prostate, skin (melanoma orbasal cell cancer) or hematological tumors (such as the leukemias) atany stage of the disease with or without metastases.

Additional non-limiting examples of cancers include, acute lymphoblasticleukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer,appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basalcell carcinoma, bile duct cancer, bladder cancer, bone cancer(osteosarcoma and malignant fibrous histiocytoma), brain stem glioma,brain tumors, brain and spinal cord tumors, breast cancer, bronchialtumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia,chronic myelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cutaneous T-Cell lymphoma, embryonal tumors,endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer,ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladdercancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumor (GIST), gastrointestinal stromal celltumor, germ cell tumor, glioma, hairy cell leukemia, head and neckcancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngealcancer, intraocular melanoma, islet cell tumors (endocrine pancreas),Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngealcancer, leukemia, Acute lymphoblastic leukemia, acute myeloid leukemia,chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cellleukemia, liver cancer, non-small cell lung cancer, small cell lungcancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma,non-Hodgkin lymphoma, lymphoma, Waldenström macroglobulinemia,medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouthcancer, chronic myelogenous leukemia, myeloid leukemia, multiplemyeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma,non-small cell lung cancer, oral cancer, oropharyngeal cancer,osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer,ovarian epithelial cancer, ovarian germ cell tumor, ovarian lowmalignant potential tumor, pancreatic cancer, papillomatosis,parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymaltumors of intermediate differentiation, pineoblastoma and supratentorialprimitive neuroectodermal tumors, pituitary tumor, plasma cellneoplasm/multiple myeloma, pleuropulmonary blastoma, primary centralnervous system lymphoma, prostate cancer, rectal cancer, renal cell(kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary glandcancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, kaposi, Sézarysyndrome, skin cancer, small cell Lung cancer, small intestine cancer,soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer,supratentorial primitive neuroectodermal tumors, T-cell lymphoma,testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroidcancer, urethral cancer, uterine cancer, uterine sarcoma, vaginalcancer, vulvar cancer, Waldenström macroglobulinemia, Wilms tumor.

The increased concentrations of LPA and vesicles in ascites from ovariancancer patients and breast cancer effussions indicate that it could bean early diagnostic marker, a prognostic indicator or an indicator ofresponse to therapy (Mills et al, Nat. Rev. Cancer., 3, 582-591, 2003;Sutphen et al., Cancer Epidemiol. Biomarkers Prev. 13, 1185-1191, 2004).LPA concentrations are consistently higher in ascites samples than inmatched plasma samples.

Respiratory and Allergic Disorders

In one aspect, LPA is a contributor to the pathogenesis of respiratorydiseases. In one aspect the respiratory disease is asthma.Proinflammatory effects of LPA include degranulation of mast cells,contraction of smooth-muscle cells and release of cytokines fromdendritic cells. Airway smooth muscle cells, epithelial cells and lungfibroblasts all show responses to LPA. LPA induces the secretion of IL-8from human bronchial epithelial cells. IL-8 is found in increasedconcentrations in BAL fluids from patients with asthma, chronicobstructive lung disease, pulmonary sarcoidosis and acute respiratorydistress syndrome and Il-8 has been shown to exacerbate airwayinflammation and airway remodeling of asthmatics. LPA₁, LPA₂ and LPA₃receptors have all been shown to contribute to the LPA-induced IL-8production. Studies cloning multiple GPCRs that are activated by LPAallowed the demonstration of the presence of mRNA for the LPA₁, LPA₂ andLPA₃ in the lung (J.J.A. Contos, et al., Mol. Pharmacol. 58, 1188-1196,2000).

The release of LPA from platelets activated at a site of injury and itsability to promote fibroblast proliferation and contraction are featuresof LPA as a mediator of wound repair. In the context of airway disease,asthma is an inflammatory disease where inappropriate airway “repair”processes lead to structural “remodeling” of the airway. In asthma, thecells of the airway are subject to ongoing injury due to a variety ofinsults, including allergens, pollutants, other inhaled environmentalagents, bacteria and viruses, leading to the chronic inflammation thatcharacterizes asthma.

In one aspect, in the asthmatic individual, the release of normal repairmediators, including LPA, is exaggerated or the actions of the repairmediators are inappropriately prolonged leading to inappropriate airwayremodeling. Major structural features of the remodeled airway observedin asthma include a thickened lamina reticularis (the basementmembrane-like structure just beneath the airway epithelial cells),increased numbers and activation of myofibroblasts, thickening of thesmooth muscle layer, increased numbers of mucus glands and mucussecretions, and alterations in the connective tissue and capillary bedthroughout the airway wall. In one aspect, LPA contributes to thesestructural changes in the airway. In one aspect, LPA is involved inacute airway hyperresponsiveness in asthma. The lumen of the remodeledasthmatic airway is narrower due to the thickening of the airway wall,thus decreasing airflow. In one aspect, LPA contributes to the long-termstructural remodeling and the acute hyperresponsiveness of the asthmaticairway. In one aspect, LPA contributes to the hyperresponsiveness thatis a primary feature of acute exacerbations of asthma.

In addition to the cellular responses mediated by LPA, several of theLPA signaling pathway components leading to these responses are relevantto asthma. EGF receptor upregulation is induced by LPA and is also seenin asthmatic airways (M. Amishima, et al., Am. J. Respir. Crit. CareMed. 157, 1907- 1912, 1998). Chronic inflammation is a contributor toasthma, and several of the transcription factors that are activated byLPA are known to be involved in inflammation (Ediger et al., Eur RespirJ 21:759-769, 2003).

In one aspect, the fibroblast proliferation and contraction andextracellular matrix secretion stimulated by LPA contributes to thefibroproliferative features of other airway diseases, such as theperibronchiolar fibrosis present in chronic bronchitis, emphysema, andinterstitial lung disease. Emphysema is also associated with a mildfibrosis of the alveolar wall, a feature which is believed to representan attempt to repair alveolar damage. In another aspect, LPA plays arole in the fibrotic interstitial lung diseases and obliterativebronchiolitis, where both collagen and myofibroblasts are increased. Inanother aspect, LPA is involved in several of the various syndromes thatconstitute chronic obstructive pulmonary disease.

Administration of LPA in vivo induces airway hyper-responsiveness,itch-scratch responses, infiltration and activation of eosinophils andneutrophils, vascular remodeling, and nociceptive flexor responses. LPAalso induces histamine release from mouse and rat mast cells. In anacute allergic reaction, histamine induces various responses, such ascontraction of smooth muscle, plasma exudation, and mucus production.Plasma exudation is important in the airway, because the leakage andsubsequent airway-wall edema contribute to the development of airwayhyperresponsiveness. Plasma exudation progresses to conjunctivalswelling in ocular allergic disorder and nasal blockage in allergicrhinitis (Hashimoto et al., J Pharmacol Sci 100, 82 - 87, 2006). In oneaspect, plasma exudation induced by LPA is mediated by histamine releasefrom mast cells via one or more LPA receptors. In one aspect, the LPAreceptor(s) include LPA₁ and/or LPA₃. In one aspect, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, is used inthe treatment of various allergic disorders in a mammal. In one aspect,a compound of Formula (I), or a pharmaceutically acceptable saltthereof, is used in the treatment of respiratory diseases, disorders orconditions in a mammal. In one aspect, a compound of Formula (I), or apharmaceutically acceptable salt thereof, is used in the treatment ofasthma in a mammal. In one aspect, a compound of Formula (I), or apharmaceutically acceptable salt thereof, is used in the treatment ofchronic asthma in a mammal.

The term “respiratory disease,” as used herein, refers to diseasesaffecting the organs that are involved in breathing, such as the nose,throat, larynx, eustachian tubes, trachea, bronchi, lungs, relatedmuscles (e.g., diaphram and intercostals), and nerves. Respiratorydiseases include, but are not limited to, asthma, adult respiratorydistress syndrome and allergic (extrinsic) asthma, non-allergic(intrinsic) asthma, acute severe asthma, chronic asthma, clinicalasthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitiveasthma, exercise-induced asthma, isocapnic hyperventilation, child-onsetasthma, adult-onset asthma, cough-variant asthma, occupational asthma,steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis,perennial allergic rhinitis, chronic obstructive pulmonary disease,including chronic bronchitis or emphysema, pulmonary hypertension,interstitial lung fibrosis and/or airway inflammation and cysticfibrosis, and hypoxia.

The term “asthma” as used herein refers to any disorder of the lungscharacterized by variations in pulmonary gas flow associated with airwayconstriction of whatever cause (intrinsic, extrinsic, or both; allergicor non-allergic). The term asthma may be used with one or moreadjectives to indicate cause.

In one aspect, presented herein is the use of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, in the treatment orprevention of chronic obstructive pulmonary disease in a mammalcomprising administering to the mammal at least once an effective amountof at least one compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. In addition, chronic obstructive pulmonarydisease includes, but is not limited to, chronic bronchitis oremphysema, pulmonary hypertension, interstitial lung fibrosis and/orairway inflammation, and cystic fibrosis.

Nervous System

The nervous system is a major locus for LPA₁ expression; there it isspatially and temporally regulated throughout brain development.Oligodendrocytes, the myelinating cells in the central nervous system(CNS), express LPA₁ in mammals. In addition, Schwann cells, themyelinating cells of the peripheral nervous system, also express LPA₁,which is involved in regulating Schwann cell survival and morphology.These observations identify important functions for receptor-mediatedLPA signaling in neurogenesis, cell survival, and myelination.

Exposure of peripheral nervous system cell lines to LPA produces a rapidretraction of their processes resulting in cell rounding, which was, inpart, mediated by polymerization of the actin cytoskeleton. In oneaspect, LPA causes neuronal degeneration under pathological conditionswhen the blood-brain barrier is damaged and serum components leak intothe brain (Moolenaar, Curr. Opin. Cell Biol. 7:203-10, 1995).Immortalized CNS neuroblast cell lines from the cerebral cortex alsodisplay retraction responses to LPA exposure through Rho activation andactomyosin interactions. In one aspect, LPA is associated withpost-ischemic neural damage (J. Neurochem. 61, 340, 1993; J. Neurochem.,70:66, 1998).

In one aspect, provided is a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment orprevention of a nervous system disorder in a mammal. The term “nervoussystem disorder,” as used herein, refers to conditions that alter thestructure or function of the brain, spinal cord or peripheral nervoussystem, including but not limited to Alzheimer’s Disease, cerebraledema, cerebral ischemia, stroke, multiple sclerosis, neuropathies,Parkinson’s Disease, those found after blunt or surgical trauma(including post-surgical cognitive dysfunction and spinal cord or brainstem injury), as well as the neurological aspects of disorders such asdegenerative disk disease and sciatica.

In one aspect, provided is a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment orprevention of a CNS disorder in a mammal. CNS disorders include, but arenot limited to, multiple sclerosis, Parkinson’s disease, Alzheimer’sdisease, stroke, cerebral ischemia, retinal ischemia, post-surgicalcognitive dysfunction, migraine, peripheral neuropathy/neuropathic pain,spinal cord injury, cerebral edema and head injury.

Cardiovascular Disorders

Cardiovascular phenotypes observed after targeted deletion oflysophospholipid receptors reveal important roles for lysophospholipidsignaling in the development and maturation of blood vessels, formationof atherosclerotic plaques and maintenance of heart rate (Ishii, I. etal. Annu. Rev. Biochem. 73, 321-354, 2004). Angiogenesis, the formationof new capillary networks from pre-existing vasculature, is normallyinvoked in wound healing, tissue growth and myocardial angiogenesisafter ischemic injury. Peptide growth factors (e.g. vascular endothelialgrowth factor (VEGF)) and lysophospholipids control coordinatedproliferation, migration, adhesion, differentiation and assembly ofvascular endothelial cells (VECs) and surrounding vascular smooth-musclecells (VSMCs). In one aspect, dysregulation of the processes mediatingangiogenesis leads to atherosclerosis, hypertension, tumor growth,rheumatoid arthritis and diabetic retinopathy (Osborne, N. and Stainier,D.Y. Annu. Rev. Physiol. 65, 23-43, 2003).

Downstream signaling pathways evoked by lysophospholipid receptorsinclude Rac-dependent lamellipodia formation (e.g. LPA₁) andRho-dependent stress-fiber formation (e.g. LPA₁), which is important incell migration and adhesion. Dysfunction of the vascular endothelium canshift the balance from vasodilatation to vasoconstriction and lead tohypertension and vascular remodeling, which are risk factors foratherosclerosis (Maguire, J.J. et al., Trends Pharmacol. Sci. 26,448-454, 2005).

LPA contributes to both the early phase (barrier dysfunction andmonocyte adhesion of the endothelium) and the late phase (plateletactivation and intra-arterial thrombus formation) of atherosclerosis, inaddition to its overall progression. In the early phase, LPA fromnumerous sources accumulates in lesions and activates its cognate GPCRs(LPA₁ and LPA₃) expressed on platelets (Siess, W. Biochim. Biophys. Acta1582, 204-215, 2002; Rother, E. et al. Circulation 108, 741-747, 2003).This triggers platelet shape change and aggregation, leading tointra-arterial thrombus formation and, potentially, myocardialinfarction and stroke. In support of its atherogenic activity, LPA canalso be a mitogen and motogen to VSMCs and an activator of endothelialcells and macrophages. In one aspect, mammals with cardiovasculardisease benefit from LPA receptor antagonists that prevent thrombus andneointima plaque formation.

In one aspect, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is used to treat or prevent cardiovasculardisease in mammal.

The term “cardiovascular disease,” as used herein refers to diseasesaffecting the heart or blood vessels or both, including but not limitedto: arrhythmia (atrial or ventricular or both); atherosclerosis and itssequelae; angina; cardiac rhythm disturbances; myocardial ischemia;myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke;peripheral obstructive arteriopathy of a limb, an organ, or a tissue;reperfusion injury following ischemia of the brain, heart or other organor tissue; endotoxic, surgical, or traumatic shock; hypertension,valvular heart disease, heart failure, abnormal blood pressure; shock;vasoconstriction (including that associated with migraines); vascularabnormality, inflammation, insufficiency limited to a single organ ortissue..

In one aspect, provided herein are methods for preventing or treatingvasoconstriction, atherosclerosis and its sequelae myocardial ischemia,myocardial infarction, aortic aneurysm, vasculitis and stroke comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (I), or a pharmaceutically acceptable saltthereof, or pharmaceutical composition or medicament which includes acompound of Formula (I), or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein are methods for reducing cardiacreperfusion injury following myocardial ischemia and/or endotoxic shockcomprising administering at least once to the mammal an effective amountof at least one compound of Formula (I), or a pharmaceuticallyacceptable salt thereof.

In one aspect, provided herein are methods for reducing the constrictionof blood vessels in a mammal comprising administering at least once tothe mammal an effective amount of at least one compound of Formula (I),or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein are methods for lowering or preventing anincrease in blood pressure of a mammal comprising administering at leastonce to the mammal an effective amount of at least one compound ofFormula (I), or a pharmaceutically acceptable salt thereof.

Inflammation

LPA has been shown to regulate immunological responses by modulatingactivities/functions of immune cells such as T-/B-lymphocytes andmacrophages. In activated T cells, LPA activates IL-2 production/cellproliferation through LPA₁ (Gardell et al, TRENDS in Molecular MedicineVol. 12 No.2 February 2006). Expression of LPA-induced inflammatoryresponse genes is mediated by LPA₁ and LPA₃ (Biochem Biophys Res Commun.363(4):1001-8, 2007). In addition, LPA modulates the chemotaxis ofinflammatory cells (Biochem Biophys Res Commun., 1993, 15;193(2), 497).The proliferation and cytokine-secreting activity in response to LPA ofimmune cells (J. Imuunol. 1999, 162, 2049), platelet aggregationactivity in response to LPA, acceleration of migration activity inmonocytes, activation of NF-κB in fibroblast, enhancement offibronectin-binding to the cell surface, and the like are known. Thus,LPA is associated with various inflammatory/immune diseases.

In one aspect, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is used to treat or prevent inflammation in amammal. In one aspect, antagonists of LPA₁ and/or LPA₃ find use in thetreatment or prevention of inflammatory/immune disorders in a mammal. Inone aspect, the antagonist of LPA₁ is a compound of Formula (I), or apharmaceutically acceptable salt thereof.

Examples of inflammatory/immune disorders include psoriasis, rheumatoidarthritis, vasculitis, inflammatory bowel disease, dermatitis,osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis,vaginitis, interstitial cystitis, scleroderma, eczema, allogeneic orxenogeneic transplantation (organ, bone marrow, stem cells and othercells and tissues) graft rejection, graft-versus-host disease, lupuserythematosus, inflammatory disease, type I diabetes, pulmonaryfibrosis, dermatomyositis, Sjogren’s syndrome, thyroiditis (e.g.,Hashimoto’s and autoimmune thyroiditis), myasthenia gravis, autoimmunehemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsinghepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopicdermatitis.

Other Diseases, Disorders or Conditions

In accordance with one aspect, are methods for treating, preventing,reversing, halting or slowing the progression of LPA-dependent orLPA-mediated diseases or conditions once it becomes clinically evident,or treating the symptoms associated with or related to LPA-dependent orLPA-mediated diseases or conditions, by administering to the mammal acompound of Formula (I), or a pharmaceutically acceptable salt thereof.In certain embodiments, the subject already has a LPA-dependent orLPA-mediated disease or condition at the time of administration, or isat risk of developing a LPA-dependent or LPA-mediated disease orcondition.

In certain aspects, the activity of LPA₁ in a mammal is directly orindirectly modulated by the administration of (at least once) atherapeutically effective amount of at least one compound of Formula(I), or a pharmaceutically acceptable salt thereof. Such modulationincludes, but is not limited to, reducing and/or inhibiting the activityof LPA₁. In additional aspects, the activity of LPA in a mammal isdirectly or indirectly modulated, including reducing and/or inhibiting,by the administration of (at least once) a therapeutically effectiveamount of at least one compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. Such modulation includes, but is not limitedto, reducing and/or inhibiting the amount and/or activity of a LPAreceptor. In one aspect, the LPA receptor is LPA₁.

In one aspect, LPA has a contracting action on bladder smooth musclecell isolated from bladder, and promotes growth of prostate-derivedepithelial cell (J. Urology, 1999, 162, 1779-1784; J. Urology, 2000,163, 1027-1032). In another aspect, LPA contracts the urinary tract andprostate in vitro and increases intraurethral pressure in vivo (WO02/062389).

In certain aspects, are methods for preventing or treating eosinophiland/or basophil and/or dendritic cell and/or neutrophil and/or monocyteand/or T-cell recruitment comprising administering at least once to themammal an effective amount of at least one compound of Formula (I), or apharmaceutically acceptable salt thereof.

In certain aspects, are methods for the treatment of cystitis,including, e.g.,interstitial cystitis, comprising administering at leastonce to the mammal a therapeutically effective amount of at least onecompound of Formula (I), or a pharmaceutically acceptable salt thereof.

In accordance with one aspect, methods described herein include thediagnosis or determination of whether or not a patient is suffering froma LPA-dependent or LPA-mediated disease or condition by administering tothe subject a therapeutically effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, and determiningwhether or not the patient responds to the treatment.

In one aspect provided herein are compounds of Formula (I),pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs,and pharmaceutically acceptable solvates thereof, which are antagonistsof LPA₁, and are used to treat patients suffering from one or moreLPA-dependent or LPA-mediated conditions or diseases, including, but notlimited to, lung fibrosis, kidney fibrosis, liver fibrosis, scarring,asthma, rhinitis, chronic obstructive pulmonary disease, pulmonaryhypertension, interstitial lung fibrosis, arthritis, allergy, psoriasis,inflammatory bowel disease, adult respiratory distress syndrome,myocardial infarction, aneurysm, stroke, cancer, pain, proliferativedisorders and inflammatory conditions. In some embodiments,LPA-dependent conditions or diseases include those wherein an absoluteor relative excess of LPA is present and/or observed.

In any of the aforementioned aspects the LPA-dependent or LPA-mediateddiseases or conditions include, but are not limited to, organ fibrosis,asthma, allergic disorders, chronic obstructive pulmonary disease,pulmonary hypertension, lung or pleural fibrosis, peritoneal fibrosis,arthritis, allergy, cancer, cardiovascular disease, ult respiratorydistress syndrome, myocardial infarction, aneurysm, stroke, and cancer.

In one aspect, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is used to improve the corneal sensitivitydecrease caused by corneal operations such as laser-assisted in situkeratomileusis (LASIK) or cataract operation, corneal sensitivitydecrease caused by corneal degeneration, and dry eye symptom causedthereby.

In one aspect, presented herein is the use of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, in the treatment orprevention of ocular inflammation and allergic conjunctivitis, vernalkeratoconjunctivitis, and papillary conjunctivitis in a mammalcomprising administering at least once to the mammal an effective amountof at least one compound of Formula (I), or a pharmaceuticallyacceptable salt thereof.

In one aspect, presented herein is the use of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, in the treatment orprevention of Sjogren disease or inflammatory disease with dry eyes in amammal comprising administering at least once to the mammal an effectiveamount of at least one compound of Formula (I), or a pharmaceuticallyacceptable salt thereof.

In one aspect, LPA and LPA receptors (e.g. LPA₁) are involved in thepathogenesis of osteoarthritis (Kotani et al, Hum. Mol. Genet., 2008,17, 1790-1797). In one aspect, presented herein is the use of a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, in thetreatment or prevention of osteoarthritis in a mammal comprisingadministering at least once to the mammal an effective amount of atleast one compound of Formula (I), or a pharmaceutically acceptable saltthereof.

In one aspect, LPA receptors (e.g. LPA₁, LPA₃) contribute to thepathogenesis of rheumatoid arthritis (Zhao et al, Mol. Pharmacol., 2008,73(2), 587-600). In one aspect, presented herein is the use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,in the treatment or prevention of rheumatoid arthritis in a mammalcomprising administering at least once to the mammal an effective amountof at least one compound of Formula (I), or a pharmaceuticallyacceptable salt thereof.

In one aspect, LPA receptors (e.g. LPA₁) contribute to adipogenesis.(Simon et al, J.Biol. Chem., 2005, vol. 280, no. 15, p.14656). In oneaspect, presented herein is the use of a compound of Formula (I), or apharmaceutically acceptable salt thereof, in the promotion of adiposetissue formation in a mammal comprising administering at least once tothe mammal an effective amount of at least one compound of Formula (I),or a pharmaceutically acceptable salt thereof.

A. In Vitro Assays

The effectiveness of compounds of the present invention as LPA₁inhibitors can be determined in an LPA₁ functional antagonist assay asfollows:

Chinese hamster ovary cells overexpressing human LPA₁ were platedovernight (15,000 cells/well) in poly-D-lysine coated 384-wellmicroplates (Greiner bio-one, Cat#781946) in DMEM/F12 medium (Gibco,Cat#11039). Following overnight culture, cells were loaded with calciumindicator dye (AAT Bioquest Inc, Cat# 34601) for 30 minutes at 37° C.The cells were then equilibrated to room temperature for 30 minutesbefore the assay. Test compounds solubilized in DMSO were transferred to384 well non-binding surface plates (Corning, Cat# 3575) using theLabcyte Echo acoustic dispense and diluted with assay buffer [1X HBSSwith calcium/magnesium (Gibco Cat# 14025-092), 20 mM HEPES (Gibco Cat#15630-080) and 0.1% fatty acid free BSA (Sigma Cat# A9205)] to a finalconcentration of 0.5% DMSO. Diluted compounds were added to the cells byFDSS6000 (Hamamatsu) at final concentrations ranging from 0.08 nM to 5µM. and were then incubated for 20 min at room temperature at which timeLPA (Avanti Polar Lipids Cat#857130C) was added at final concentrationsof 10 nM to stimulate the cells. The compound IC₅₀ value was defined asthe concentration of test compound which inhibited 50% of the calciumflux induced by LPA alone. IC₅₀ values were determined by fitting datato a 4-parameter logistic equation (GraphPad Prism, San Diego CA).

B. In Vivo Assays

LPA Challenge with plasma histamine evaluation.

Compound is dosed orally p.o. 2 hours to CD-1 female mice prior to theLPA challenge. The mice are then dosed via tail vein (IV) with 0.15 mLof LPA in 0.1%BSA/ PBS (2 µg/µL). Exactly 2 minutes following the LPAchallenge, the mice are euthanized by decapitation and the trunk bloodis collected. These samples are collectively centrifuged and individual75 µL samples are frozen at -20° C. until the time of the histamineassay.

The plasma histamine analysis was run by standard EIA (EnzymeImmunoassay) methods. Plasma samples were thawed and diluted 1:30 in0.1% BSA in PBS. The EIA protocol for histamine analysis as outlined bythe manufacturer was followed (Histamine EIA, Oxford BiomedicalResearch, EA#31).

The LPA used in the assay is formulated as follows: LPA(1-oleoyl-2-hydroxy-sn-glycero-3-phosphate (sodium salt), 857130P,Avanti Polar Lipids) is prepared in 0.1%BSA/PBS for total concentrationof 2 µg/µL. 13 mg of LPA is weighed and 6.5 mL 0.1%BSA added, vortexedand sonicated for ~1 hour until a clear solution is achieved.

V. Pharmaceutical Compositions, Formulations and Combinations

In some embodiments, provided is a pharmaceutical composition comprisinga therapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof. In some embodiments, thepharmaceutical composition also contains at least one pharmaceuticallyacceptable inactive ingredient.

In some embodiments, provided is a pharmaceutical composition comprisinga therapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable inactive ingredient. In one aspect, thepharmaceutical composition is formulated for intravenous injection,subcutaneous injection, oral administration, inhalation, nasaladministration, topical administration, ophthalmic administration orotic administration. In some embodiments, the pharmaceutical compositionis a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spraysolution, a suppository, a suspension, a gel, a colloid, a dispersion, asuspension, a solution, an emulsion, an ointment, a lotion, an eye dropor an ear drop.

In some embodiments, the pharmaceutical composition further comprisesone or more additional therapeutically active agents selected from:corticosteroids (e.g., dexamethasone or fluticasone), immunosuppresants(e.g., tacrolimus & pimecrolimus), analgesics, anti-cancer agent,anti-inflammatories, chemokine receptor antagonists, bronchodilators,leukotriene receptor antagonists (e.g., montelukast or zafirlukast),leukotriene formation inhibitors, monoacylglycerol kinase inhibitors,phospholipase A₁ inhibitors, phospholipase A₂ inhibitors, andlysophospholipase D (lysoPLD) inhibitors, autotaxin inhibitors,decongestants, antihistamines (e.g., loratidine), mucolytics,anticholinergics, antitussives, expectorants, anti-infectives (e.g.,fusidic acid, particularly for treatment of atopic dermatitis),anti-fungals (e.g., clotriazole, particularly for atopic dermatitis),anti-IgE antibody therapies (e.g., omalizumab), β-2 adrenergic agonists(e.g., albuterol or salmeterol), other PGD2 antagonists acting at otherreceptors such as DP antagonists, PDE4 inhibitors (e.g., cilomilast),drugs that modulate cytokine production, e.g., TACE inhibitors, drugsthat modulate activity of Th2 cytokines IL-4 & IL-5 (e.g., blockingmonoclonal antibodies & soluble receptors), PPARγ agonists (e.g.,rosiglitazone and pioglitazone), 5-lipoxygenase inhibitors (e.g.,zileuton).

In some embodiments, the pharmaceutical composition further comprisesone or more additional anti-fibrotic agents selected from pirfenidone,nintedanib, thalidomide, carlumab, FG-3019, fresolimumab, interferonalpha, lecithinized superoxide dismutase, simtuzumab, tanzisertib,tralokinumab, hu3G9, AM-152, IFN-gamma-1b, IW-001, PRM-151, PXS-25,pentoxifylline/N-acetyl-cysteine, pentoxifylline/vitamin E, salbutamolsulfate, [Sar9,Met(O2)11]-Substance P, pentoxifylline, mercaptaminebitartrate, obeticholic acid, aramchol, GFT-505, eicosapentaenoic acidethyl ester, metformin, metreleptin, muromonab-CD3, oltipraz, IMM-124-E,MK-4074, PX-102, RO-5093151. In some embodiments, provided is a methodcomprising administering a compound of Formula (I), or apharmaceutically acceptable salt thereof, to a human with aLPA-dependent or LPA-mediated disease or condition. In some embodiments,the human is already being administered one or more additionaltherapeutically active agents other than a compound of Formula (I), or apharmaceutically acceptable salt thereof. In some embodiments, themethod further comprises administering one or more additionaltherapeutically active agents other than a compound of Formula (I), or apharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutically activeagents other than a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, are selected from: corticosteroids (e.g,.dexamethasone or fluticasone), immunosuppresants (e.g., tacrolimus &pimecrolimus), analgesics, anti-cancer agent, anti-inflammatories,chemokine receptor antagonists, bronchodilators, leukotriene receptorantagonists (e.g., montelukast or zafirlukast), leukotriene formationinhibitors, monoacylglycerol kinase inhibitors, phospholipase A₁inhibitors, phospholipase A₂ inhibitors, and lysophospholipase D(lysoPLD) inhibitors, autotaxin inhibitors, decongestants,antihistamines (e.g., loratidine), mucolytics, anticholinergics,antitussives, expectorants, anti-infectives (e.g., fusidic acid,particularly for treatment of atopic dermatitis), anti-fungals (e.g.,clotriazole, particularly for atopic dermatitis), anti-IgE antibodytherapies (e.g., omalizumab), β-2 adrenergic agonists (e.g., albuterolor salmeterol), other PGD2 antagonists acting at other receptors such asDP antagonists, PDE4 inhibitors (e.g., cilomilast), drugs that modulatecytokine production, e.g. TACE inhibitors, drugs that modulate activityof Th2 cytokines IL-4 & IL-5 (e.g., blocking monoclonal antibodies &soluble receptors), PPARγ agonists (e.g., rosiglitazone andpioglitazone), 5-lipoxygenase inhibitors (e.g., zileuton).

In some embodiments, the one or more additional therapeutically activeagents other than a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, are other anti-fibrotic agents selected frompirfenidone, nintedanib, thalidomide, carlumab, FG-3019, fresolimumab,interferon alpha, lecithinized superoxide dismutase, simtuzumab,tanzisertib, tralokinumab, hu3G9, AM-152, IFN-gamma-1b, IW-001, PRM-151,PXS-25, pentoxifylline/N-acetyl-cysteine, pentoxifylline/vitamin E,salbutamol sulfate, [Sar9,Met(O2)11]-Substance P, pentoxifylline,mercaptamine bitartrate, obeticholic acid, aramchol, GFT-505,eicosapentyl ethyl ester, metformin, metreleptin, muromonab-CD3,oltipraz, IMM-124-E, MK-4074, PX-102, RO-5093151.

In some embodiments, the one or more additional therapeutically activeagents other than a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, are selected from ACE inhibitors, ramipril, AIIantagonists, irbesartan, anti-arrythmics, dronedarone, PPARα activators,PPARγ activators, pioglitazone, rosiglitazone, prostanoids, endothelinreceptor antagonists, elastase inhibitors, calcium antagonists, betablockers, diuretics, aldosterone receptor antagonists, eplerenone, renininhibitors, rho kinase inhibitors, soluble guanylate cyclase (sGC)activators, sGC sensitizers, PDE inhibitors, PDE5 inhibitors, NO donors,digitalis drugs, ACE/NEP inhibitors, statins, bile acid reuptakeinhibitors, PDGF antagonists, vasopressin antagonists, aquaretics, NHE1inhibitors, Factor Xa antagonists, Factor XIIIa antagonists,anticoagulants, anti-thrombotics, platelet inhibitors, profibroltics,thrombin-activatable fibrinolysis inhibitors (TAFI), PAI-1 inhibitors,coumarins, heparins, thromboxane antagonists, serotonin antagonists, COXinhibitors, aspirin, therapeutic antibodies, GPIIb/IIIa antagonists, ERantagonists, SERMs, tyrosine kinase inhibitors, RAF kinase inhibitors,p38 MAPK inhibitors, pirfenidone, multi-kinase inhibitors, nintedanib,sorafenib.

In some embodiments, the one or more additional therapeutically activeagents other than a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, are selected from Gremlin-1 mAb, PA1-1 mAb,Promedior (PRM-151; recombinant human Pentraxin-2); FGF21, TGFβantagonists, αvβ6 & αvβ pan-antagonists; FAK inhibitors, TG2 inhibitors,LOXL2 inhibitors, NOX4 inhibitors, MGAT2 inhibitors, GPR120 agonists.

Pharmaceutical formulations described herein are administrable to asubject in a variety of ways by multiple administration routes,including but not limited to, oral, parenteral (e.g., intravenous,subcutaneous, intramuscular), intranasal, buccal, topical or transdermaladministration routes. The pharmaceutical formulations described hereininclude, but are not limited to, aqueous liquid dispersions,self-emulsifying dispersions, solid solutions, liposomal dispersions,aerosols, solid dosage forms, powders, immediate release formulations,controlled release formulations, fast melt formulations, tablets,capsules, pills, delayed release formulations, extended releaseformulations, pulsatile release formulations, multiparticulateformulations, and mixed immediate and controlled release formulations.

In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered orally.

In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered topically. In such embodiments,the compound of Formula (I), or a pharmaceutically acceptable saltthereof, is formulated into a variety of topically administrablecompositions, such as solutions, suspensions, lotions, gels, pastes,shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages,balms, creams or ointments. Such pharmaceutical compounds can containsolubilizers, stabilizers, tonicity enhancing agents, buffers andpreservatives. In one aspect, the compound of Formula (I), or apharmaceutically acceptable salt thereof, is administered topically tothe skin.

In another aspect, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered by inhalation. In oneembodiment, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered by inhalation that directlytargets the pulmonary system.

In another aspect, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is formulated for intranasal administration.Such formulations include nasal sprays, nasal mists, and the like.

In another aspect, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is formulated as eye drops.

In another aspect is the use of a compound of Formula (I), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for treating a disease, disorder or conditions in which theactivity of at least one LPA receptor contributes to the pathologyand/or symptoms of the disease or condition. In one embodiment of thisaspect, the LPA is selected from LPA₁, LPA₂, LPA₃, LPA₄, LPA₅ and LPA₆.In one aspect, the LPA receptor is LPA₁. In one aspect, the disease orcondition is any of the diseases or conditions specified herein.

In any of the aforementioned aspects are further embodiments in which:(a) the effective amount of the compound of Formula (I), or apharmaceutically acceptable salt thereof, is systemically administeredto the mammal; and/or (b) the effective amount of the compound isadministered orally to the mammal; and/or (c) the effective amount ofthe compound is intravenously administered to the mammal; and/or (d) theeffective amount of the compound is administered by inhalation; and/or(e) the effective amount of the compound is administered by nasaladministration; or and/or (f) the effective amount of the compound isadministered by injection to the mammal; and/or (g) the effective amountof the compound is administered topically to the mammal; and/or (h) theeffective amount of the compound is administered by ophthalmicadministration; and/or (i) the effective amount of the compound isadministered rectally to the mammal; and/or (j) the effective amount isadministered non-systemically or locally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce; (ii) the compound is administered to the mammal multiple timesover the span of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

Also provided is a method of inhibiting the physiological activity ofLPA in a mammal comprising administering a therapeutically effectiveamount of a compound of Formula (I) or a pharmaceutically acceptablesalt thereof to the mammal in need thereof.

In one aspect, provided is a medicament for treating a LPA-dependent orLPA-mediated disease or condition in a mammal comprising atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof.

In some cases disclosed herein is the use of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of a LPA-dependent or LPA-mediated diseaseor condition.

In some cases disclosed herein is the use of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, in the treatment orprevention of a LPA-dependent or LPA-mediated disease or condition.

In one aspect, is a method for treating or preventing a LPA-dependent orLPA-mediated disease or condition in a mammal comprising administering atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof.

In one aspect, LPA-dependent or LPA-mediated diseases or conditionsinclude, but are not limited to, fibrosis of organs or tissues,scarring, liver diseases, dermatological conditions, cancer,cardiovascular disease, respiratory diseases or conditions, inflammatorydisease, gastrointestinal tract disease, renal disease, urinarytract-associated disease, inflammatory disease of lower urinary tract,dysuria, frequent urination, pancreas disease, arterial obstruction,cerebral infarction, cerebral hemorrhage, pain, peripheral neuropathy,and fibromyalgia.

In one aspect, the LPA-dependent or LPA-mediated disease or condition isa respiratory disease or condition. In some embodiments, the respiratorydisease or condition is asthma, chronic obstructive pulmonary disease(COPD), pulmonary fibrosis, pulmonary arterial hypertension or acuterespiratory distress syndrome.

In some embodiments, the LPA-dependent or LPA-mediated disease orcondition is selected from idiopathic pulmonary fibrosis; other diffuseparenchymal lung diseases of different etiologies including iatrogenicdrug-induced fibrosis, occupational and/or environmental inducedfibrosis, granulomatous diseases (sarcoidosis, hypersensitivitypneumonia), collagen vascular disease, alveolar proteinosis, langerhanscell granulomatosis, lymphangioleiomyomatosis, inherited diseases(Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis,metabolic storage disorders, familial interstitial lung disease);radiation induced fibrosis; chronic obstructive pulmonary disease(COPD); scleroderma; bleomycin induced pulmonary fibrosis; chronicasthma; silicosis; asbestos induced pulmonary fibrosis; acuterespiratory distress syndrome (ARDS); kidney fibrosis;tubulointerstitium fibrosis; glomerular nephritis; focal segmentalglomerular sclerosis; IgA nephropathy; hypertension; Alport; gutfibrosis; liver fibrosis; cirrhosis; alcohol induced liver fibrosis;toxic/drug induced liver fibrosis; hemochromatosis; nonalcoholicsteatohepatitis (NASH); biliary duct injury; primary biliary cirrhosis;infection induced liver fibrosis; viral induced liver fibrosis; andautoimmune hepatitis; corneal scarring; hypertrophic scarring; Duputrendisease, keloids, cutaneous fibrosis; cutaneous scleroderma; spinal cordinjury/fibrosis; myelofibrosis; vascular restenosis; atherosclerosis;arteriosclerosis; Wegener’s granulomatosis; Peyronie’s disease, chroniclymphocytic leukemia, tumor metastasis, transplant organ rejection,endometriosis, neonatal respiratory distress syndrome and neuropathicpain.

In one aspect, the LPA-dependent or LPA-mediated disease or condition isdescribed herein.

In one aspect, provided is a method for the treatment or prevention oforgan fibrosis in a mammal comprising administering a therapeuticallyeffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof to a mammal in need thereof.

In one aspect, the organ fibrosis comprises lung fibrosis, renalfibrosis, or hepatic fibrosis.

In one aspect, provided is a method of improving lung function in amammal comprising administering a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereofto the mammal in need thereof. In one aspect, the mammal has beendiagnosed as having lung fibrosis.

In one aspect, compounds disclosed herein are used to treat idiopathicpulmonary fibrosis (usual interstitial pneumonia) in a mammal.

In some embodiments, compounds disclosed herein are used to treatdiffuse parenchymal interstitial lung diseases in mammal: iatrogenicdrug induced, occupational/environmental (Farmer lung), granulomatousdiseases (sarcoidosis, hypersensitivity pneumonia), collagen vasculardisease (scleroderma and others), alveolar proteinosis, langerhans cellgranulonmatosis, lymphangioleiomyomatosis, Hermansky-Pudlak Syndrome,Tuberous sclerosis, neurofibromatosis, metabolic storage disorders,familial interstitial lung disease.

In some embodiments, compounds disclosed herein are used to treatpost-transplant fibrosis associated with chronic rejection in a mammal:Bronchiolitis obliterans for lung transplant.

In some embodiments, compounds disclosed herein are used to treatcutaneous fibrosis in a mammal: cutaneous scleroderma, Dupuytrendisease, keloids.

In one aspect, compounds disclosed herein are used to treat hepaticfibrosis with or without cirrhosis in a mammal: toxic/drug induced(hemochromatosis), alcoholic liver disease, viral hepatitis (hepatitis Bvirus, hepatitis C virus, HCV), nonalcoholic liver disease (NAFLD,NASH), metabolic and auto-immune disease.

In one aspect, compounds disclosed herein are used to treat renalfibrosis in a mammal: tubulointerstitium fibrosis, glomerular sclerosis.

In any of the aforementioned aspects involving the treatment of LPAdependent diseases or conditions are further embodiments comprisingadministering at least one additional agent in addition to theadministration of a compound having the structure of Formula (I), or apharmaceutically acceptable salt thereof. In various embodiments, eachagent is administered in any order, including simultaneously.

In any of the embodiments disclosed herein, the mammal is a human.

In some embodiments, compounds provided herein are administered to ahuman.

In some embodiments, compounds provided herein are orally administered.

In some embodiments, compounds provided herein are used as antagonistsof at least one LPA receptor. In some embodiments, compounds providedherein are used for inhibiting the activity of at least one LPA receptoror for the treatment of a disease or condition that would benefit frominhibition of the activity of at least one LPA receptor. In one aspect,the LPA receptor is LPA₁.

In other embodiments, compounds provided herein are used for theformulation of a medicament for the inhibition of LPA₁ activity.

Articles of manufacture, which include packaging material, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, within thepackaging material, and a label that indicates that the compound orcomposition, or pharmaceutically acceptable salt, tautomers,pharmaceutically acceptable N-oxide, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate thereof, is used for inhibiting the activity of at least one LPAreceptor, or for the treatment, prevention or amelioration of one ormore symptoms of a disease or condition that would benefit frominhibition of the activity of at least one LPA receptor, are provided.

VI. General Synthesis Including Schemes

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene et al., (Protective Groups in Organic Synthesis,Fourth Edition, Wiley-Interscience (2006)).

The compounds of Formula (I) may be prepared by the exemplary processesdescribed in the following schemes and working examples, as well asrelevant published literature procedures that are used by one skilled inthe art. Exemplary reagents and procedures for these reactions appearherein after and in the working examples. Protection and deprotection inthe processes below may be carried out by procedures generally known inthe art (see, for example, Wuts, P.G.M., Greene’s Protective Groups inOrganic Synthesis, 5th Edition, Wiley (2014)). General methods oforganic synthesis and functional group transformations are found in:Trost, B.M. et al., Eds., Comprehensive Organic Synthesis: Selectivity,Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, NewYork, NY (1991); Smith, M.B. et al., March’s Advanced Organic Chemistry:Reactions, Mechanisms, and Structure. 7th Edition, Wiley, New York, NY(2013); Katritzky, A.R. et al., Eds., Comprehensive Organic FunctionalGroup Transformations II, 2nd Edition, Elsevier Science Inc., Tarrytown,NY (2004); Larock, R.C., Comprehensive Organic Transformations, 2^(nd)Edition, Wiley-VCH, New York, NY (1999), and references therein.

Scheme 1 describes the synthesis of N-carbamoyl-triazole-aryloxycyclohexyl acids 16 & 17. A dihalo (preferably dibromo) phenyl or azine(e.g. pyridine) derivative 1 is coupled with an appropriately protected(e.g. as a tetrahydropyranyl ether) propargyl alcohol 2 underSonogashira conditions (e.g. Alper, P. et al, WO 2008097428) to give thecorresponding bromo-aryl or bromo-heteroaryl protected propargyl alcohol3. Thermal reaction of alkyne 3 with an alkyl azide 4 (with or withoutan appropriate catalyst; Qian, Y. et al, J. Med. Chem., 2012, 55,7920-7939 or Boren, B. C., et al., J. Am. Chem. Soc., 2008, 130,8923-8930) provides the corresponding regioisomeric protectedhydroxylmethyl-triazoles, from which the desired triazole regioisomer 5can be isolated. Reaction of the bromoaryl- or bromoheteroaryl-triazoles5 with bis-pinacol diboronate in the presence of an appropriatepalladium catalyst (Ishiyama, T. et al, J. Org. Chem. 1995, 60,7508-7510) provides the corresponding pinacol boronate 6, which is thenoxidized with hydrogen peroxide to give the corresponding phenol orhydroxyheteroarene 7 (Fukumoto, S. et al, WO 2012137982). Reaction ofphenol/hydroxyheteroarene 7 with a 3-hydroxy cycloalkyl ester 8 (e.g.cyclohexyl) under Mitsunobu reaction conditions (Kumara Swamy, K. C.,Chem. Rev., 2009, 109, 2551-2651) furnishes the corresponding triazolecycloalkyl ether ester 9. Deprotection of the hydoxytriazole 9 providesthe triazole alcohol 10, which is then reacted with a brominating agent(e.g. PBr₃ or CBr₄/Ph₃P) to give the triazole bromide 11. Displacementof bromide 11 with NaN₃ (or an equivalent azide reagent) furnishes thetriazole azide 12, which is reduced (e.g. Staudinger reduction withPh₃P/H₂O) to give the triazole amine 13. Amine 13 is then reacted withan acylating agent 14 (e.g. a chloroformate or a 4-nitrophenylcarbonate) in the presence of an appropriate base to give thecorresponding NH-carbamate 15. Ester deprotection of triazole 15provides the desired triazole-carbamate cycloalkyl acids 16. Treatmentof the triazole NH-carbamate 16 with an appropriate base (e.g. NaH orNaN(TMS)₂) and halide R³X provides the corresponding N-alkylatedcarbamate-cycloalkyl ester, which is deprotected by base-mediatedhydrolysis to give triazole N-carbamoyl cycloalkyl acids 17.

For the specific example of analogs 20, where R₂ = CH₃ (Scheme 1A),instead of using an alkyl azide for the cycloaddition to the protectedhydroxyalkyl alkyne 3, trimethylsilyl azide is a viable replacementreagent (Qian, Y. et al, J. Med. Chem., 2012, 55, 7920-7939) that can beused under either thermal or transition-metal catalyzed conditions(Boren, B.C. et. al., J. Am. Chem. Soc., 2008, 130, 8923-8930). Underthese conditions, the desired triazole regioisomer 18 is obtained as themajor product of the 1,3-dipolar cycloaddition reaction. Thetrimethylsilyl group of 18 is removed under standard desilylationconditions (e.g. Bu₄NF, as in Qian, Y. et al, J. Med. Chem., 2012, 55,7920-7939) to give the N-methyl triazole 19 (corresponding to 5, whereR⁵ = CH₃), which is then converted to N-carbamoyl triazole cyclohexylacids 20 according to the synthetic sequences described in Scheme 1(i.e. from 5 → 16 & 17).

Scheme 2 describes an alternative synthetic route to the N-carbamoyltriazole-aryloxy cyclohexyl acids 16 or 17. A dihalo (preferablydibromo) phenyl or azine (e.g. pyridine) derivative 1 is coupled withpropargyl alcohol under Sonogashira conditions (Alper, P. et al, WO2008097428) to give the corresponding bromo-aryl or bromo-heteroarylpropargyl alcohol 21. Thermal reaction of alkyne 21 with an alkyl azide4 (with or without an appropriate catalyst, Qian, Y. et al, J. Med.Chem., 2012, 55, 7920-7939; Boren, B.C. et. al., J. Am. Chem. Soc.,2008, 130, 8923-8930) provides the corresponding regioisomerichydroxymethyl-triazoles, from which the desired triazole regioisomer 22can be isolated. Triazole alcohol 18 is then reacted with a brominatingagent (e.g. PBr₃ or CBr₄/Ph₃P) to give the corresponding bromide 23.Displacement of bromide 23 with NaN₃ (or other appropriate azidereagents) gives azide 24, which undergoes reduction (e.g. Staudingerreduction with Ph₃P/H₂O) to afford triazole amine 25. Protection of thetriazole amine 25 gives intermediate 26. The bromo-aryl/heteroaryltriazole 26 is then converted to the correspondinghydroxy-aryl/heteroaryl triazole 27 via the corresponding boronate usingthe same 2 step sequence [borylation with B₂(pin)₂/Pd catalyst followedby H₂O₂-mediated oxidation of the boronate] as described in Scheme 1.The hydroxyaryl triazole 27 then is subjected to a Mitsunobu reactionwith a 3-hydroxy cycloalkyl ester 8 to furnish the correspondingtriazole cycloalkyl ether ester 28. The amine 28 is deprotected to givethe key triazole amine intermediate 13, which is then converted to theN-carbamate acids 16 or 17 by the synthetic sequences described inScheme 1.

Scheme 3 describes an alternative synthetic route to the triazoleN-carbamate cyclohexyl acids 16 and 17. Reaction of the triazole amine25 with an acylating reagent 14 in the presence of base affords triazoleN-carbamate 29. The bromo-aryl/heteroaryl triazole 29 is converted tothe corresponding hydroxyaryl/heteroaryl triazole 30 via thecorresponding boronate using the 2 step sequence [B₂(pin)₂/Pd-catalystfollowed by H₂O₂ oxidation] as described in Scheme 1.Hydroxyaryl/heteroaryl triazole 30 is subjected to a Mitsunobu reactionwith a 3-hydroxy cycloalkylester 8 to furnish the corresponding triazoleN-carbamate cycloalkyl ester 15. This key triazole N-carbamateintermediate 15 is then converted to N-carbamate acids 16 & 17 asdescribed in Scheme 1.

Scheme 4 describes an alternative synthetic route to the triazoleN-carbamate cyclohexyl acids 16 and 17. Reaction of an alkoxyphenyl orazine (e.g. pyridine or pyrazine) derivative 31 with trimethylsilylacetylene under Sonogashira conditions (Alper, P. et al, WO 2008097428)gives the corresponding alkoxy-aryl or heteroaryl silyl acetylene, whichis then desilylated under standard conditions (e.g. Bu₄NF) to give thealkyne 32. Thermal reaction of alkyne 32 with sodium azide gives thecorresponding triazole (Roehrig, U. et al, WO 2009127669), which is thenalkylated with an alkyl iodide 25 in the presence of base to give amixture of regioisomeric alkylated triazoles, from which the desiredtriazole regioisomer 33 can be isolated. Metalation of triazole 33 withan appropriate lithiating agent (e.g. Hernandez, M. et al, US20120115844) followed by formylation (e.g. with dimethyl formamide)provides the triazole aldehyde 34. Deprotection of the alkoxy group ofarene/heteroarene 34 followed by reprotection of thephenol/hydroxy-heteroarene with a more labile protecting group (e.g. at-butyldimethylsilyl ether) gives the protected aryl/heteroaryl triazolealdehyde 35, which is then reduced by standard methods (e.g. NaBH₄) tothe corresponding triazole alcohol 36. Triazole alcohol 36 is convertedto the triazole amine 37 by the same 3-step sequence as described inScheme 1 (10 → 13). The triazole amine 37 is then reacted with anacylating reagent 14 in the presence of base, then is deprotected toafford the triazole N-carbamate 30. The key hydroxyaryl/heteroaryltriazole intermediate 30 is then converted to N-carbamate acids 16 & 17as described in Scheme 3.

Scheme 5 describes the synthesis of N-carbamoyl triazole-aryloxyα-fluoro cyclohexyl acids 44 and 45. Diels-Alder reaction of1,3-butadiene and an appropriately protected 2-fluoroacrylate ester(e.g. procedure of Kotikyan et al., Bull. Acad. Sci. USSR, Division ofChemical Science (Engl.), 1971, 20, 292) gives the α-F cyclohexyl ester38. Deprotection of ester 38 (e.g. hydrolysis) provides acid 39.Iodolactonization (e.g. Nolsøe, J. M. J. et al., Eur. J. Org. Chem.,2014, 3051-3065) of the alkene with the carboxylic acid of 38 givesiodolactone 39. Radical-mediated deiodination (e.g. AIBN/(TMS)₃SiH, ref.Chatgilialoglu, C. et al., Molecules, 2012, 17, 527-555) orhydrogenolysis conditions affords lactone 41. Acid-mediated ring openingof lactone 41 in the presence of an alcohol gives the protectedα-fluoro-cyclohexyl ester 42. Hydroxyester 42 then undergoes a Mitsunobureaction with hydroxyaryl/hydroxy-heteroaryl-triazole 7 to give thecorresponding cyclohexyl ether triazole ester 43 as described inScheme 1. The N-carbamoyl methyltriazole-aryloxy α-fluoro-cyclohexylacids 44 and 45 are synthesized from the α-fluoro-cyclohexyl triazoleester 43 following the general synthetic procedures described in Scheme1.

Scheme 6 describes the synthesis of N-carbamoyl methyltriazole-aryloxycyclohexyl acids 44 and 45. Addition of an alkyl organometallic reagent(e.g R^(7a)Li or R^(7a)MgX) to aldehyde 35 gives triazole alcohol 46,which is then protected as 47. Deprotection of thehydroxyarene/hydroxy-heteroarene, followed by Mitsunobu reaction with 8,provides cyclohexyl ether triazole 48. Deprotection of 48 furnishesalcohol 49, which can be carried forward to cyclohexylN-carbamate-triazole acids 50 and 51 following the general syntheticprocedure described in Scheme 1.

Scheme 7 describes the synthesis of directly-linked N-carbamoyl triazoleacids 54 and 55. Oxidation of cyclohexyl ether triazole-alcohol 10 tothe carboxylic acid 52 (e.g. directly to the acid with pyridiniumdichromate or via a 2-step procedure via the aldehyde [Swern oxidationor Dess-Martin periodinane followed by NaClO₂ oxidation to the acid,e.g. Lindgren, B. O., Acta Chem. Scand. 1973, 27, 888]). Curtiusrearrangement of 52 in the presence of an alcohol R⁴—OH provides thetriazole NH-carbamate 53. Deprotection of the triazole NH-carbamateester 53 provides the triazole NH-carbamate acids 54. AlternativelyNH-carbamate cyclohexyl ester 53 is deprotonated with a suitable baseand alkylated (as in Scheme 1) with an alkyl R³-halide to give thetriazole N-alkyl carbamate acids 55.

Scheme 8 describes the synthesis of N-carbamoyl triazole-aryloxycyclohexyl acids 59 and 60. Triazole alcohol 10 is oxidized to thecorresponding aldehyde (e.g. Dess-Martin periodinane or Swernoxidation), which is then subjected to an olefination reaction (e.g.Wittig or Peterson olefination reaction) which provides the terminalolefin 56. Hydroboration of olefin 56 at the terminal carbon (e.g. with9-BBN), followed by oxidative workup, provides the correspondingtriazole ethyl alcohol 57. Triazole ethyl alcohol 57 undergoes the3-step sequence described in Scheme 1 (bromination, azide displacement,azide reduction) to give the key intermediate triazole-ethylamine 58.The triazole-ethylamine 58 is then carried forward totriazole-ethyl-N-carbamate cyclohexyl acids 59 and 60 using the samesynthetic sequence described for the conversion of amine 13 to triazolecarbamate-acids 16 and 17 in Scheme 1.

Scheme 9 describes the synthesis of N-ureido-triazole-aryloxy cyclohexylacids 63 and 65. Triazole amine cyclohexyl ester 13 undergoes reactionwith a carbamoyl chloride 62 (prepared, e.g., from the reaction of asecondary amine 61 with triphosgene) to give the correspondingureido-triazole cyclohexyl ester, which is then deprotected to providethe N,N′-dialkyl-ureido-triazole-aryloxy cyclohexyl acids 63. In acomplementary synthetic route, triazole amine cyclohexyl ester 13undergoes reaction directly with triphosgene to give the carbamoylchloride 64 (CDI to give the corresponding intermediate), which isreacted with a primary amine R³—NH₂ (or with a secondary amine 61) togive (after ester deprotection) the correspondingN-alkyl-ureido-triazole aryloxy cyclohexyl acids 65 (with secondaryamines the products are the N,N′-dialkyl ureido-triazole acids 63).

Scheme 10 describes the synthesis of triazole-N-linked urea cyclohexylacids 67 and 68. Cyclohexyl ether triazole-alcohol 10 undergoesoxidation to the triazole carboxylic acid 66 (e.g. directly to the acidwith e.g. pyridinium dichromate or via a 2-step procedure via thealdehyde [Swern oxidation or Dess-Martin periodinane followed by NaClO₂oxidation to the acid, e.g. Lindgren, B. O., Acta Chem. Scand. 1973, 27,888]). Curtius rearrangement (e.g. with (PhO)₂PON₃) of triazole acid 66furnishes the corresponding intermediate triazole isocyanate, which isthen reacted with either a primary amine R³NH₂ or a secondary amineR³R⁴NH to give, after ester deprotection, thetriazole-ureido-NH-alkyl-cyclohexyl acids 67 or thetriazole-ureido-N,N-dialkyl-cyclohexyl acids 68.

Scheme 11 describes the synthesis of triazole-sulfonylureido cyclohexylacids 70. Triazole amine cyclohexyl ester 13 undergoes reaction with adialkyl sulfamoyl chloride 69 (prepared from the reaction of a secondaryamine 61 with sulfuryl chloride) to give the correspondingsulfonylureido-triazole cyclohexyl ester, which is then deprotected toprovide the sulfonylureido-triazole-aryloxy cyclohexyl acids 70.

VII. EXAMPLES

The following Examples are offered as illustrative, as a partial scopeand particular embodiments of the invention and are not meant to belimiting of the scope of the invention. Abbreviations and chemicalsymbols have their usual and customary meanings unless otherwiseindicated. Unless otherwise indicated, the compounds described hereinhave been prepared, isolated and characterized using the schemes andother methods disclosed herein or may be prepared using the same.

As appropriate, reactions were conducted under an atmosphere of drynitrogen (or argon). For anhydrous reactions, DRISOLV® solvents from EMwere employed. For other reactions, reagent grade or HPLC grade solventswere utilized. Unless otherwise stated, all commercially obtainedreagents were used as received.

Microwave reactions were carried out using a 400 W Biotage Initiatorinstrument in microwave reaction vessels under microwave (2.5 GHz)irradiation.

HPLC/MS and preparatory/analytical HPLC methods employed incharacterization or purification of examples

NMR (nuclear magnetic resonance) spectra were typically obtained onBruker or JEOL 400 MHz and 500 MHz instruments in the indicatedsolvents. All chemical shifts are reported in ppm from tetramethylsilanewith the solvent resonance as the internal standard. ¹HNMR spectral dataare typically reported as follows: chemical shift, multiplicity (s =singlet, br s = broad singlet, d = doublet, dd = doublet of doublets, t= triplet, q = quartet, sep = septet, m = multiplet, app = apparent),coupling constants (Hz), and integration.

In the examples where ¹H NMR spectra were collected in d₆-DMSO, awater-suppression sequence is often utilized. This sequence effectivelysuppresses the water signal and any proton peaks in the same regionusually between 3.30-3.65 ppm which will affect the overall protonintegration.

The term HPLC refers to a Shimadzu high performance liquidchromatography instrument with one of following methods:

HPLC-1: Sunfire C18 column (4.6 × 150 mm) 3.5 µm, gradient from 10 to100% B:A for 12 min, then 3 min hold at 100% B.

-   Mobile phase A: 0.05% TFA in water:CH₃CN (95:5)-   Mobile phase B: 0.05% TFA in CH₃CN:water (95:5)-   TFA Buffer pH = 2.5; Flow rate: 1 mL/ min; Wavelength: 254 nm, 220    nm.

HPLC-2: XBridge Phenyl (4.6 × 150 mm) 3.5 µm, gradient from 10 to 100%B:A for 12 min, then 3 min hold at 100% B.

-   Mobile phase A: 0.05% TFA in water:CH₃CN (95:5)-   Mobile phase B: 0.05% TFA in CH₃CN:water (95:5)-   TFA Buffer pH = 2.5; Flow rate: 1 mL/ min; Wavelength: 254 nm, 220    nm.

HPLC-3: Chiralpak AD-H, 4.6 × 250 mm, 5 µm.

-   Mobile Phase: 30% EtOH-heptane (1:1) / 70% CO₂-   Flow rate = 40 mL/min, 100 Bar, 35° C.; Wavelength: 220 nm

HPLC-4: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-µm particles;

-   Mobile Phase A: 5:95 CH₃CN:water with 10 mM NH₄OAc;-   Mobile Phase B: 95:5 CH₃CN:water with 10 mM NH₄OAc;-   Temperature: 50° C.; Gradient: 0-100% B over 3 min, then a 0.75-min    hold at 100% B; Flow: 1.11 mL/min; Detection: UV at 220 nm.

HPLC-5: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7-µm particles;

-   Mobile Phase A: 5:95 CH₃CN:water with 0.1% TFA;-   Mobile Phase B: 95:5 CH₃CN:water with 0.1% TFA;-   Temperature: 50° C.; Gradient: 0-100% B over 3 min, then a 0.75-min    hold at 100%-   B; Flow: 1.11 mL/min; Detection: UV at 220 nm.

Intermediate 1 (±)-cis-isopropyl1-fluoro-3-hydroxycyclohexanecarboxylate

Intermediate 1A. (±)-ethyl 1-fluorocyclohex-3-enecarboxylate

A mixture of 20% buta-1,3-diene in toluene (13.8 mL, 41.1 mmol) andethyl 2-fluoroacrylate (3.07 mL, 27.4 mmol) was heated at 120° C. in asealed tube for 7 days, then was cooled to RT and concentrated in vacuo.The residue was chromatographed (80 g SiO₂; continuous gradient from 0%to 10% EtOAc in hexane over 20 min) to give Intermediate 1A (3.80 g,22.1 mmol, 80 % yield) as a clear oil. ¹H NMR (500 MHz, CDCl₃) δ 5.79(ddd, J=9.9, 4.7, 2.2 Hz, 1H), 5.64 - 5.58 (m, 1H), 4.26 (q, J=7.2 Hz,2H), 2.73 - 2.57 (m, 1H), 2.45 - 2.23 (m, 2H), 2.20 - 1.91 (m, 3H), 1.32(t, J=7.2 Hz, 3H); ¹⁹F NMR (471 MHz, CDCl₃) δ -162.69 (s, 1F).

Intermediate 1B. (±)-1-fluorocyclohex-3-ene carboxylic acid

A mixture of Intermediate 1A (3.80 g, 22.1 mmol) and aq. LiOH (55.2 mLof a 2.0 M solution, 110 mmol) in THF (50 mL) was stirred at RT for 18h. The reaction was acidified to pH = 2 with conc. HCl (9.19 mL, 110mmol), and then extracted with EtOAc (3 x 25 mL). The combined organicextracts were washed with water and concentrated in vacuo to giveIntermediate 1B (3.0 g, 20.8 mmol, 94 % yield) as a light yellowish oil.¹H NMR (500 MHz, CDCl₃) δ 5.81 (ddd, J=9.8, 4.6, 2.1 Hz, 1H), 5.66 -5.58 (m, 1H), 2.76 -2.59 (m, 1H), 2.49 - 2.37 (m, 1H), 2.35 - 2.23 (m,1H), 2.22 - 1.92 (m, 3H); ¹⁹F NMR (471 MHz, CDCl₃) δ -163.02 (s, 1F).

Intermediate 1C. (±)-1-fluoro-4-iodo-6-oxabicyclo[3.2.1]octan-7-one

To a mixture of Intermediate 1B (3.0 g, 20.8 mmol) in water (20 mL) wasadded NaHCO₃ (5.25 g, 62.4 mmol) portionwise and the mixture was stirreduntil it became homogeneous. An aq. I₂ solution (prepared by dissolvingI₂ (5.81 g, 22.0 mmol) and KI (20.7 g, 125 mmol) in 20 mL water) wasadded and the reaction was stirred overnight at RT in the dark. Water(100 mL) was then added and the mixture was extracted with DCM (3 x 25mL), washed with 10% aq. Na₂S₂O₃ (20 mL x 2) and water, dried (MgSO₄)and concentrated in vacuo. The residual crude oil was chromatographed(80 g SiO₂; continuous gradient from 0% to 50% EtOAc in hexane over 20min) to give Intermediate 1C (3.53 g, 13.1 mmol, 62.8 % yield) as awhite solid. ¹H NMR (500 MHz, CDCl₃) δ 4.89 (dt, J=6.5, 3.5 Hz, 1H),4.44 (q, J=4.6 Hz, 1H), 3.08 (dd, J=11.6, 1.9 Hz, 1H), 2.75 (tddd,J=11.3, 6.5, 3.3, 1.1 Hz, 1H), 2.50 - 2.38 (m, 1H), 2.34 - 2.17 (m, 2H),2.11 - 1.99 (m, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 172.2, 172.0, 93.6,91.9, 78.4, 78.3, 39.2, 39.0, 29.7, 29.6, 28.4, 28.2, 20.2; ¹⁹F NMR (471MHz, CDCl₃) δ -167.97 (s, 1F).

Intermediate 1D. (±)-1-fluoro-6-oxabicyclo[3.2.1]octan-7-one

To a solution of intermediate 1C (350 mg, 1.30 mmol) and AIBN (21 mg,0.130 mmol) in benzene (5 mL) was added tris(trimethylsilyl)silane (0.60mL, 1.94 mmol) portionwise over 10 min at 60° C. The reaction wasstirred at 70° C. for 2 h, cooled to RT and then concentrated in vacuo.The residue was dissolved in EtOAc, washed with sat. aq. NH₄Cl, dried(MgSO₄) and concentrated in vacuo. The crude oil was chromatographed (12g SiO₂; continuous gradient from 0% to 30% EtOAc in hexane over 10 min)to give Intermediate 1D (124 mg, 0.860 mmol, 66.4 % yield) as a whitesolid. ¹⁹F NMR (471 MHz, CDCl₃) δ -167.01 (s, 1F); ¹H NMR (500 MHz,CDCl₃) δ 4.98 - 4.81 (m, 1H), 2.75 (dtdd, J=15.9, 6.8, 3.3, 1.7 Hz, 1H),2.24 - 1.89 (m, 5H), 1.82 - 1.65 (m, 1H), 1.60 - 1.46 (m, 1H); ¹³C NMR(126 MHz, CDCl₃) δ 173.2, 173.0, 93.9, 92.3, 75.6, 75.5, 42.0, 41.9,31.3, 31.1, 26.7, 17.7, 17.6.

Intermediate 1

Acetyl chloride (0.061 mL, 0.860 mmol) was added portionwise toisopropanol (3 mL) at 0° C. and then stirred at rt for 30 min.Intermediate 1D (124 mg, 0.860 mmol) was added and the reaction wasstirred overnight at RT, then was concentrated in vacuo. The residualcrude oil was chromatographed (4 g SiO₂; continuous gradient from 0% to50% EtOAc in hexane over 10 min) to give Intermediate 1 (140 mg, 0.685mmol, 80 % yield) as a clear oil. ¹H NMR (500 MHz, CDCl₃) δ 5.08 (spt,J=6.3 Hz, 1H), 3.91 (tt, J=10.9, 4.4 Hz, 1H), 2.68 (br. s., 1H), 2.28(dddt, J=13.5, 9.0, 4.6, 2.1 Hz, 1H), 2.06 - 1.98 (m, 1H), 1.96 - 1.87(m, 1H), 1.82 - 1.62 (m, 4H), 1.37 - 1.22 (m, 7H); ¹⁹F NMR (471 MHz,CDCl₃) δ -162.93 (s, 1F); ¹³C NMR (126 MHz, CDCl₃) δ 170.9, 170.7, 95.7,94.2, 69.3, 66.1, 40.7, 40.5, 33.9, 31.6, 31.4, 21.5, 19.1.

Example 1(1S,3S)((2-Methyl-6-(1-Methyl-5-(((((S)-2-Methylbutoxy)Carbonyl)Amino)Methyl)-1H-1,2,3-Triazol-4-yl)Pyridinyl)oxy)CyclohexanecarboxylicAcid

1A.3-Bromo-2-Methyl-6-(3-((Tetrahydro-2H-Pyran-2-yl)oxy)Prop-1-yn-1-yl)Pyridine

To a solution of 2,5-dibromo-6-methyl-pyridine (5 g, 21.11 mmol) and2-(prop-2-yn-1-yloxy) tetrahydro-2H-pyran (4.44 g, 31.7 mmol) in MeCN(42.2 mL) was added Et₃N (8.83 mL, 63.3 mmol). The solution was degassedunder N₂, then (Ph₃P)₂PdCl₂ (0.74 g, 1.06 mmol) and CuI (0.20 g, 1.06mmol) were added. The reaction was stirred at RT for 14 h, after whichthe reaction mixture was filtered through a Celite® plug and the plugwas washed with EtOAc (2 X 10 mL). The combined filtrates wereconcentrated in vacuo and the residue was chromatographed (SiO₂;continuous gradient from 0% to 100% EtOAc in hexanes for 20 min) to givethe title compound as a white solid (6.0 g, 20.3 mmol, 96% yield). ¹HNMR (400 MHz, CDCl₃) δ 8.65 (d, J=2.0 Hz, 1H), 7.80 (dd, J=8.3, 2.3 Hz,1H), 7.35 (dd, J=8.4, 0.4 Hz, 1H), 4.91 (t, J=3.3 Hz, 1H), 4.61 - 4.45(m, 2H), 3.98 - 3.81 (m, 1H), 3.66 - 3.44 (m, 1H), 1.92 - 1.73 (m, 2H),1.72 - 1.52 (m, 2H). LCMS, [M+H]⁺ = 298.0.

1B.3-Bromo-2-Methyl-6-(1-Methyl-5-(((Tetrahydro-2H-Pyran-2-yl)oxy)Methyl)-1H-1,2,3-Triazol-4-yl)Pyridine

A solution of Example 1A (6.0 g, 20.3 mmol) in toluene (20 mL) andTMSCH₂N₃ (7.85 g, 60.8 mmol) was heated at 90° C. under Ar for 15 h,then was cooled to RT. Volatiles were removed in vacuo and the residuewas dissolved in THF (20 mL). To the mixture was added TBAF (20.3 mL ofa 1 M solution in THF, 20.3 mmol) at 0° C. After stirring for 10 min,the reaction was complete as determined by analytical HPLC. Volatileswere removed in vacuo and the residue was chromatographed (SiO₂;continuous gradient from 0% to 100% EtOAc in hexanes over 20 min) togive the title compound (2.1 g, 29% yield) as a white solid. ¹H NMR (400MHz, CDCl₃) δ 7.85 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.03 (br.s., 1H), 5.39 - 5.23 (m, 4H), 4.81 - 4.76 (m, 1H), 4.17 (s, 3H), 3.91(ddd, J=11.3, 7.9, 3.3 Hz, 1H), 3.65 - 3.48 (m, 1H), 2.54 (s, 3H), 1.88-1.68 (m, 2H), 1.56 (br. s., 2H).

1C.2-Methyl-6-(1-Methyl-5-(((Tetrahydro-2H-Pyran-2-yl)oxy)Methyl)-1H-1,2,3-Triazol-4-yl)Pyridin-3-ol

To a degassed solution (sparged with Ar 3X) of Example 1B (213 mg, 0.60mmol), bis(pinacolato)diboron (230 mg, 0.91 mmol) and KOAc (178 mg, 1.81mmol) in THF was added Pd(dppf)Cl₂ (22 mg, 0.03 mmol). The reactionmixture was heated in a sealed tube at 80° C. for 16 h, then was cooledto RT and partitioned between water and EtOAc. The aqueous layer wasextracted with EtOAc (3 X 20 mL). The combined organic extracts werewashed with brine, dried (MgSO₄) and concentrated in vacuo. The crudeboronate product was carried on to the next step without furtherpurification. To a solution of the crude product,2-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(241 mg, 0.603 mmol) in EtOAc (2 mL) was added H₂O₂ (0.19 mL of a 30%aqueous solution, 6.0 mmol). The reaction mixture was stirred at RT for1 h, then was cooled to 0° C. and quenched by slowly adding sat. aq.Na₂S₂O₃. The aqueous layer was extracted with EtOAc (3 X 20 mL). Thecombined organic extracts were washed with brine, dried (MgSO₄),filtered and concentrated in vacuo. The residue was chromatographed(SiO₂ ISCO column, continuous gradient from 0% to 100% EtOAc in hexanesover 20 min) to give the title compound (150 mg, 86%) as as a whitesolid. ¹H NMR (400 M Hz, CDCl₃) δ 8.27 (d, J=2.6 Hz, 1H), 8.06 (d, J=8.6Hz, 1H), 7.29 - 7.21 (m, 1H), 5.33 (s, 1H), 5.28 (d, J=2.4 Hz, 2H), 4.76(s, 1H), 4.18 (s, 3H), 3.90 (s, 1H), 3.63 - 3.48 (m, 1H), 1.72 (s, 2H),1.65 - 1.51 (m, 2H). LCMS, [M+H]⁺ = 291.2.

1D. Isopropyl(1S,3S)-3-((2-Methyl-6-(1-Methyl-5-(((Tetrahydro-2H-Pyran-2-yl)oxy)Methyl)-1H-1,2,3-Triazol-4-yl)Pyridin-3-yl)oxy)Cyclohexane-1-Carboxylate

To a solution of Example 1C (1.18 g, 4.06 mmol) and (1S, 3R)-isopropyl3-hydroxy cyclohexanecarboxylate (synthesized according to the proceduredescribed in US2007/0197788A1, 1.51 g, 8.13 mmol) in toluene (81 mL) wasadded Bu₃P (3.17 mL, 12.2 mmol). To this stirred mixture was added(E)-diazene-1,2-diylbis(piperidin-1-yl-methanone) (3.08 g, 12.2 mmol)portionwise, and the reaction mixture was heated at 50° C. for 120 min,then was cooled to RT. At this point an LC-MS spectrum of the reactionmixture showed the presence of the desired product. The mixture wasfiltered and the filtrate was concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 0% to 100% EtOAc inhexanes over 20 min) to give the title compound (1.2 g, 2.62 mmol, 64.4% yield) as a white foam. ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J=8.6 Hz,1H), 7.22 (d, J=8.6 Hz, 1H), 5.45 - 5.24 (m, 2H), 5.04 (dt, J=12.5, 6.3Hz, 1H), 4.83 - 4.64 (m, 2H), 4.16 (s, 3H), 3.91 (ddd, J=11.2, 7.9, 3.1Hz, 1H), 3.64 - 3.48 (m, 1H), 2.93 - 2.71 (m, 1H), 2.52 (s, 3H), 2.23 -1.45 (m, 14H), 1.26 (dd, J=6.4, 2.0 Hz, 6H).

1E. Isopropyl(1S,3S)-3-((6-(5-(Hydroxymethyl)-1-Methyl-1H-1,2,3-Triazol-4-yl)-2-Methylpyridin-3-yl)oxy)Cyclohexane-1-Carboxylate

To a solution of Example 1D (1.7 g, 3.71 mmol) in MeOH (37 mL) was addedPPTS (0.932 g, 3.71 mmol). The reaction mixture was heated to 60° C. for2 h, then was cooled to RT, diluted with water and satd aq. NaHCO₃, thenextracted with EtOAc (3 X 10 mL). The combined organic extracts weredried (Na₂SO₄), concentrated in vacuo and chromatographed (SiO₂;continuous gradient from 0% to 100% EtOAc in hexanes over 20 min) togive the title compound as a white foam (1.36 g, 3.63 mmol, 98% yield).¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, J=8.6 Hz, 1H), 7.46 (d, J=5.1 Hz,1H), 7.27 - 7.15 (m, 1H), 4.96 (dt, J=12.5, 6.3 Hz, 1H), 4.74 (s, 2H),4.66 - 4.59 (m, 1H), 4.00 (s, 3H), 2.80 - 2.64 (m, 1H), 2.46 (s, 3H),2.07 - 1.50 (m, 8H), 1.18 (dd, J=6.4, 2.2 Hz, 6H).

1F. (1S,3S)-Isopropyl3-((6-(5-(Bromomethyl)-1-Methyl-1H-1,2,3-Triazol-4-yl)-2-Methylpyridin-3-yl)oxy)Cyclohexanecarboxylate

To a solution of Example 1E (0.28 g, 0.721 mmol) in DME (7 mL) was addedPBr₃ (0.17 mL, 1.80 mmol) at 0° C. The reaction was stirred overnight atRT, then was cooled to 0° C. and neutralized with sat. aq. NaHCO₃ to pH= ~7. The mixture was partitioned between EtOAc (50 mL) and water (5mL), and the aqueous layer was extracted with EtOAc (3 x 10 mL). Thecombined organic extracts were dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed (12 g SiO₂; continuous gradient from 0%to 50% of EtOAc/hexanes over 25 min) to give the title compound (300 mg,0.665 mmol, 92% yield) as a white solid. LCMS, [M + H]⁺ = 451.2. ¹H NMR(500 MHz, CDCl₃) δ 7.99 (d, J=8.5 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 5.26(d, J=1.4 Hz, 2H), 5.03 (spt, J=6.3 Hz, 1H), 4.75 - 4.63 (m, 1H), 4.12(s, 3H), 2.82 - 2.74 (m, 1H), 2.54 (s, 3H), 2.14 - 2.07 (m, 1H), 1.99 -1.88 (m, 3H), 1.81 - 1.59 (m, 4H), 1.27 - 1.24 (m, 6H)

1G. (1S,3S)-Isopropyl3-((6-(5-(Azidomethyl)-1-Methyl-1H-1,2,3-Triazol-4-yl)-2-Methylpyridin-3-yl)oxy)Cyclohexanecarboxylate

To a solution of Example 1F (100 mg, 0.222 mmol) in DMF (1.5 mL) wasadded NaN₃ (36 mg, 0.554 mmol) and the reaction was stirred at 80° C.for 1 h, then was cooled to RT. LCMS analysis indicated that thereaction was complete. The reaction mixture was partitioned betweenEtOAc and water, and the mixture was stirred at RT for 15 min. Theorganic layer was dried (Na₂SO₄) and concontrated in vacuo to give thecrude title compound, which was used in the next step without furtherpurification. LCMS, [M + H]⁺ = 414.3.

1H. (1S,3S)-Isopropyl3-((6-(5-(Aminomethyl)-1-Methyl-1H-1,2,3-Triazol-4-yl)-2-Methylpyridin-3-yl)oxy)Cyclohexanecarboxylate

To a solution of Example 1G (92 mg, 0.22 mmol) in THF (1 mL) and H₂O(0.3 mL) was added Ph₃P (58 mg, 0.22 mmol) and the reaction was stirredat RT overnight. The reaction mixture was partitioned between EtOAc andwater, and the resulting mixture was stirred at RT for 15 min. Theorganic layer was dried (Na₂SO₄) and concentrated in vacuo. The residuewas chromatographed (12 g SiO₂; 100% EtOAc for 10 min and then agradient from 0% to 10% MeOH in CH₂Cl₂ over 20 min; flow rate = 30mL/min) to give the title compound (81 mg, 0.21 mmol, 94% yield) as abeige oil. LCMS, [M + H]⁺ = 388.3.

Example 1

To a solution of Example 1H (8 mg, 0.021 mmol) and (S)-2-methylbutyl(4-nitrophenyl) carbonate (7 mg, 0.027 mmol) in THF (0.4 mL) was addedN-ethyl-N-isopropylpropan-2-amine (11 µL, 0.062 mmol). The mixture wasstirred at RT for 1 h, after which THF (0.8 mL)/H₂O (0.4 mL)/MeOH (0.4mL) and LiOH.H₂O (5 mg, 0.105 mmol) were added. The reaction mixture wasstirred at RT overnight, then was concentrated in vacuo and diluted withH₂O (5 mL). The pH of the mixture was adjusted with 1N aq. HCl to ~5 andextracted with EtOAc (3 x 5 mL). The combined organic extracts werewashed with brine (2 mL), dried (MgSO₄) and concentrated in vacuo. Theresidual crude product was purified by preparative LC/MS. Column: WatersXBridge C18, 19 x 200 mm, 5-µm particles; Guard Column: Waters XBridgeC18, 19 x 10 mm, 5-µm particles; Mobile Phase A: 5:95 MeCN:H₂O with 0.1%TFA; Mobile Phase B: 95:5 MeCN:H₂O with 0.1% TFA; Gradient: 50-90% Bover 20 min, then a 5 min hold at 100% B; Flow: 20 mL/min. Fractionscontaining the desired product were concentrated in vacuo by centrifugalevaporation to provide the title compound (6.6 mg, 0.014 mmol, 68%yield). LCMS, [M + H]⁺ = 460.3. ¹H NMR (500 MHz, DMSO-d₆) δ 7.80 (d,J=8.2 Hz, 1H), 7.55 (br. s., 1H), 7.46 (d, J=8.7 Hz, 1H), 4.80 - 4.62(m, 3H), 4.02 (s, 3H), 3.76 - 3.67 (m, 2H), 2.62 - 2.55 (m, 1H), 2.42(s, 3H), 2.04 - 0.93 (m, 11H), 0.83 - 0.72 (m, 6H). hLPA₁ IC₅₀ = 18 nM.

Example 2(1S,3S)((2-Methyl-6-(1-Methyl-5-((Methyl(((S)-2-Methylbutoxy)Carbonyl)aAmino)Methyl)-1H-1,2,3-Triazol-4-yl)Pyridinyl)oxy)Cyclohexanecarboxylic Acid

To a 0° C. mixture of Example 1 compound (1.7 mg, 3.70 µmol) in DMF (0.2mL) under N₂ was added NaH (0.5 mg of a 60 % dispersion in mineral oil;0.011 mmol) and the reaction was stirred for 30 min at 0° C. MeI (0.7µL, 0.011 mmol) was then added and the reaction was stirred at RT for 1h, then was concentrated in vacuo. The residue was dissolved in THF (0.8mL)/MeOH (0.4 mL)/water (0.4 mL) and LiOH.H₂O (1 mg, 18.5 µmol) wasadded at RT. The reaction mixture was stirred at RT overnight, then wasconcentrated in vacuo and diluted with H₂O (5 mL). The pH of the mixturewas adjusted with 1N aq. HCl to ~5 and the mixture was extracted withEtOAc (3 x 5 mL). The combined organic extracts were washed with brine(2 mL), dried (MgSO₄) and concentrated in vacuo. This crude product waspurified by preparative LC/MS: Column: Waters XBridge C18, 19 x 200 mm,5-µm particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-µmparticles; Mobile Phase A: 5:95 MeCN:H₂O with 0.1% TFA; Mobile Phase B:95:5 MeCN:H₂O with 0.1% TFA; Gradient: 50-90% B over 20 min, then a 5min hold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were concentrated in vacuo by centrifugal evaporation to providethe title compound (1 mg, 2.1 µmol, 56.5 % yield). LCMS, [M + H]⁺ =474.0. ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (d, J=8.2 Hz, 1H), 7.48 (d,J=8.5 Hz, 1H), 5.09 (br. s., 2H), 4.78 - 4.68 (m, 1H), 4.04 - 3.76 (m,5H), 2.73 (s, 3H), 2.65 - 2.56 (m, 1H), 2.40 (s, 3H), 1.98 - 1.02 (m,11H), 0.82 (br. s., 6H). hLPA₁ IC₅₀ = 29 nM.

Example 3(1S,3S)((6-(5-(((Butoxycarbonyl)Amino)Methyl)-1-Methyl-1H-1,2,3-Triazol-4-yl)-2-Methylpyridinyl)oxy)Cyclohexane-1-CarboxylicAcid

3A. Isopropyl(1S,3S)-3-((6-(5-(((Butoxycarbonyl)Amino)Methyl)-1-Methyl-1H-1,2,3-Triazol-4-yl)-2-Methylpyridin-3-yl)oxy)Cyclohexane-1-Carboxylate

To a solution of Example 1H (10 mg, 0.026 mmol) in EtOAc (0.3 mL) andsat. aq. NaHCO3 (0.3 mL) was added n-butyl chloroformate (0.017 mL,0.129 mmol) at RT. The reaction mixture was stirred overnight, then wasconcentrated in vacuo. This crude product was used in the next stepwithout further purification. LCMS, [M + H]⁺ = 488.3.

Example 3

To a solution of crude Example 3A (12.7 mg, 0.026 mmol) in THF (0.8mL)/H₂O (0.400 mL)/MeOH (0.400 mL) was added LiOH.H₂O (6 mg, 0.13 mmol)at RT. The mixture was stirred at RT overnight, then was concentrated invacuo; the residue was diluted with H₂O (5 mL), and the pH was adjustedwith 1N aq. HCl to ~5. The mixture was extracted with EtOAc (3 x 5 mL).The combined organic extracts were washed with brine (2 mL), dried(MgSO₄) and concentrated in vacuo. The crude product was purified bypreparative HPLC (Phenomenex Luna Axia 5 µ C18 30 x 100 mm; 10 mingradient from 85% A: 15% B to 0% A:100% B (A =90% H₂O/10% ACN + 0.1%TFA); (B = 90% ACN/10% H₂O + 0.1% TFA); detection at 220 nm) to give thetitle compound (11.3 mg, 0.025 mmol, 98% yield). -¹H NMR (500 MHz,CDCl₃) δ 8.14 (d, J=8.8 Hz, 1H), 7.92 (d, J=9.1 Hz, 1H), 4.90 - 4.81 (m,1H), 4.59 (s, 2H), 4.20 (s, 3H), 4.08 (t, J=6.6 Hz, 2H), 2.95 - 2.83 (m,1H), 2.75 (s, 3H), 2.23 - 2.13 (m, 1H), 2.03 - 1.76 (m, 6H), 1.73 -1.55(m, 3H), 1.42 - 1.31 (m, 2H), 0.92 (t, J=7.4 Hz, 3H). LCMS, [M + H]⁺ =446.3. hLPA₁ IC₅₀ = 14 nM.

Example 4(±)-(Trans)-3-(4-(5-((((Isopentyloxy)Carbonyl)Amino)Methyl)-1-Methyl-1H-1,2,3-Triazol-4-yl)Phenoxy)Cyclohexane-1-CarboxylicAcid

4A. 2-((4-Bromophenyl)Prop-2-yn-1-yl)oxy)Tetrahydro-2H-Pyran

To a solution of 1-bromo-4-iodobenzene (10.0 g, 35.3 mmol) in DMF (50mL) was added TEA (25 mL, 177 mmol), CuI (0.40 g, 2.12 mmol), Pd(Ph₃P)₄(0.82 g, 0.71 mmol) and 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (6.44g, 46.0 mmol). The reaction mixture was stirred at RT under N₂ for 16 h,then was concentrated in vacuo. The residue was chromatographed (120 gSiO₂; isocratic hexanes/EtOAc = 95:5) to afford the title compound (10.0g, 33.9 mmol, 96 % yield) as a colorless oil. LCMS, [M + Na]⁺= 319.0. ¹HNMR (500 MHz, CDCl₃) δ 7.46 - 7.42 (m, 2H), 7.33 - 7.29 (m, 2H), 4.89(t, J=3.4 Hz, 1H), 4.54 - 4.40 (m, 2H), 3.89 (ddd, J=11.5, 9.0, 2.9 Hz,1H), 3.61 - 3.54 (m, 1H), 1.92 -1.51 (m, 6H).

4B.4-Bromophenyl)-5-(((Tetrahydro-2H-Pyran-2-yl)oxy)Methyl)-1-((Trimethylsilyl)Methyl)-1H-1,2,3-Triazole

To a solution of 4A (3.0 g, 10.2 mmol) in toluene (10 mL) was addedTMSCH₂N₃ (1.8 mL, 12.2 mmol). The mixture was refluxed under Ar for 15h, then was cooled to RT and concentrated in vacuo. The crude residuewas chromatographed (120 SiO₂; continuous gradient from 0 to 20% EtOAcin hexane over 25 min, then hold at 20% EtOAc for 20 min) to give thetitle compound (667 mg, 1.57 mmol, 15% yield) as a beige solid. LCMS,[M + H]⁺ = 424.1. ¹H NMR (500 MHz, CDCl₃) δ 7.73 - 7.69 (m, 2H), 7.60 -7.56 (m, 2H), 4.84 (d, J=12.9 Hz, 1H), 4.70 - 4.64 (m, 2H), 3.87 - 3.79(m, 3H), 3.58 - 3.49 (m, 1H), 1.88 - 1.51 (m, 6H), 0.23 (s, 9H).

4C.4-Bromophenyl)-1-Methyl-5-(((Tetrahydro-2H-Pyran-2-yl)oxy)Methyl)-1H-1,2,3-Triazole

To a solution of Example 4B (660 mg, 1.56 mmol) in THF (10 mL) was addedH₂O (0.06 mL, 3.1 mmol) and the reaction was cooled to 0° C. TBAF (1.87mL of a 1.0 M solution in THF; 1.87 mmol) was added and the reaction wasstirred at 0° C. for 10 min. Volatiles were removed in vacuo and thecrude product was chromatographed (40 g SiO₂; continuous gradient from100% hexane to 50:50 hexane:EtOAc over 30 min, hold at 50% hexane:EtOAcfor 10 min) to give the title compound (510 mg, 1.49 mmol, 93% yield) asa beige oil. LCMS, [M + H]⁺ = 352.0. ¹H NMR (500 MHz, CDCl₃) δ 7.70-7.66 (m, 2H), 7.61 - 7.57 (m, 2H), 4.87 (d, J=12.9 Hz, 1H), 4.74 - 4.65(m, 2H), 4.15 (s, 3H), 3.82 (ddd, J=11.3, 8.1, 3.2 Hz, 1H), 3.58 - 3.49(m, 1H), 1.88 - 1.50 (m, 6H).

4D.4-Methyl-5-(((Tetrahydro-2H-Pyran-2-yl)oxy)Methyl)-1H-1,2,3-Triazol-4-yl)Phenol

A mixture of Pd₂(dba)₃ (44 mg, 0.048 mmol),di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (81mg, 0.191 mmol), KOH (268 mg, 4.77 mmol), and Example 4C (281 mg, 0.80mmol) in 1,4-dioxane (3 mL) and water (3 mL) was quickly evacuated undervacuum and backfilled with Ar (repeated 3X). The mixture was stirred at85° C. for 16 h, then was cooled to RT and carefully acidified withdilute aq. 1N HCl. The mixture was extracted with EtOAc (4 x 5 mL). Thecombined organic extracts were dried (MgSO₄) and concentrated in vacuoto afford the crude product as a brown solid. This material waschromatographed (SiO₂; EtOAc/hexanes) to provide the title compound (210mg, 0.726 mmol, 91% yield) as a white solid. LCMS, [M + H]⁺ = 290.1.

4E. (±)-Trans-1,3-Isopropyl3-(4-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylate(diastereomeric mixture at tetrahydropyranyl ether)

To a 0° C. mixture of 4D (0.19 g, 0.64 mmol), (±)-isopropylcis-3-hydroxy cyclohexane-1-carboxylate (0.21 g, 1.15 mmol), Et₃N (0.16mL, 1.15 mmol) and Ph₃P (0.30 g, 1.15 mmol) in THF (4 mL) was added DIAD(0.22 mL, 1.15 mmol) dropwise. The reaction was stirred overnight at RT.Water (4 mL) was added and the reaction mixture was acidified with 1 Naq. HCl and extracted with EtOAc (3 X 10 mL). The combined organicextracts were washed with brine, dried (MgSO₄) and concentrated invacuo. The crude product was chromatographed (40 g SiO₂; continuousgradient from 0% to 80% EtOAc in hexanes for 30 min and at 80%EtOAc/hexanes for 20 min) to give the title compound (0.12 g, 0.257mmol, 40% yield) as a beige oil. LCMS, [M + H]⁺ = 458.1.

4F. (±)-Trans-1,3-Isopropyl3-(4-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylate

To a solution of Example 4E (115 mg, 0.251 mmol) in MeOH (2.5 mL) wasadded PPTS (6 mg, 0.025 mmol). The reaction was stirred overnight at RT.LCMS showed that the reaction was still incomplete, so the mixture washeated at 60° C. for another 6 h, then was cooled to RT. The mixture wasconcentrated in vacuo and the residue was chromatographed (12 g SiO₂;continuous gradient from 80-100% EtOAc in hexanes over 10 min) to givethe title compound (84 mg, 90% yield) as a brown oil. LCMS, [M + H]⁺ =374.2.

4G. (±)-Trans-1,3-Isopropyl3-(4-(5-(bromomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylate

To a 0° C. mixture of Example 4F (84 mg, 0.225 mmol) and CBr₄ (82 mg,0.247 mmol) in DCM (1.2 mL) was added portionwise Ph₃P (65 mg, 0.247mmol). The reaction was allowed to slowly warm to RT overnight, then wasconcentrated in vacuo. The residue was chromatographed (12 g SiO₂; 25min continuous gradient from 0% to 70% EtOAc in hexane; flow rate = 30mL/min). The pure fractions were concentrated in vacuo to give the titlecompound (66 mg, 0.151 mmol, 67% yield) as a colorless oil. LCMS, [M +H]⁺ = 436.0.

4H. (±)-Trans-1,3-Isopropyl3-(4-(5-(azidomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylate

To a solution of Example 4G (65 mg, 0.149 mmol) in DMF (1 mL) was addedNaN₃ (24 mg, 0.37 mmol) and the reaction was stirred at 80° C. for 1 h,then was cooled to RT. LCMS analysis indicated the reaction wascomplete. The reaction mixture was partitioned between EtOAc and water(5 mL each) and the resulting mixture was stirred at RT. After 15 min,the organic layer was dried (Na₂SO₄) and concentrated in vacuo. Thecrude azide product was used in the next step without furtherpurification.

4I. (±)-Trans-1,3-Isopropyl3-(4-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)phenoxy)cyclohexanecarboxylate

To a solution of Example 4H (59 mg, 0.149 mmol) in THF (0.6 mL) and H₂O(0.2 mL) was added Ph₃P (39 mg, 0.149 mmol) and the reaction was stirredat RT overnight. The reaction mixture was partitioned between EtOAc andwater (5 mL each), and the resulting mixture was stirred at RT. After 15min, the organic layer was dried (Na₂SO₄), and concontrated in vacuo.The residue was chromatographed (8 g SiO₂; 100% EtOAc for 10 min, then acontinuous gradient of 0% to 10% MeOH in CH₂Cl₂ over 15 min; flow rate =30 mL/min) to give the title compound (47 mg, 0.126 mmol, 84% yield) asa beige oil. LCMS, [M + H]⁺ = 373.1

Example 4

A solution of 3-methylbutan-1-ol (6 mg, 0.064 mmol), CDI (11 mg, 0.064mmol) and LiOH.H₂O (3 mg, 0.11 mmol) in toluene (0.5 mL) was stirred at60° C. for 2 h. To this mixture was added Example 4I (8 mg, 0.021 mmol)and the reaction was stirred at 60° C. overnight, then was cooled to RT.The mixture was partitioned between EtOAc and water; the aqueous phasewas extracted with EtOAc (3X), and the combined organic extracts weredried (MgSO₄) and concentrated in vacuo. To a solution of this crudeproduct in THF (0.8 mL) and H₂O (0.40 mL) and MeOH (0.40 mL) was addedLiOH.H₂O (7 mg, 0.168 mmol) at RT. The reaction was stirred at RTovernight, then was concentrated in vacuo and diluted with H₂O (5 mL).The mixture was adjusted with aq. 1N HCl to pH ~3 and extracted withEtOAc (3 x 5 mL). The combined organic extracts were washed with brine(2 mL), dried (MgSO₄) and concentrated in vacuo. The crude product waspurified by preparative LC/MS: Column: Waters XBridge C18, 19 x 200 mm,5-µm particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-µmparticles; Mobile Phase A: 5:95 MeCN:H₂O with 0.1% TFA; Mobile Phase B:95:5 MeCN:H₂O with 0.1% TFA; Gradient: 50-90% B over 20 min, then a5-min hold at 100% B; Flow rate: 20 mL/min) to give the title compound(1.4 mg, 3.15 µmol, 15% yield). LCMS, [M + H]⁺ = 445.1. ¹H NMR (500 MHz,DMSO-d₆) δ 7.77 (br. s., 1H), 7.63 (d, J=7.6 Hz, 2H), 7.02 (d, J=8.5 Hz,2H), 4.72 - 4.64 (m, 1H), 4.41 (d, J=5.2 Hz, 2H), 4.06 - 3.94 (m, 5H),2.70 - 2.59 (m, 1H), 1.98 - 1.34 (m, 11H), 0.86 (d, J=6.1 Hz, 6H). hLPA₁IC₅₀ = 148 nM.

Example 5(1S,3S)((6-(5-(((Butoxycarbonyl)amino)methyl)-1-methyl-1H-1,2,3-Triazol-4-yl)Pyridinyl)oxy)Cyclohexane-1-CarboxylicAcid

5A. 3-Bromopyridin-2-yl)Prop-2-yn-1-ol

To a solution of 3,6-dibromopyridine (25.0 g, 100 mmol)) andprop-2-yn-1-ol (8.70 mL, 149 mmol) in MeCN (141 mL) was added Et₃N (33.2mL, 240 mmol). The solution was degassed under Ar (sparged with Ar 3X),after which (Ph₃P)₂PdCl₂ (2.96 g, 4.22 mmol) and CuI (0.804 g, 4.22mmol) were added. The reaction was stirred at RT under Ar for 14 h,after which the mixture was filtered through a Celite® plug, which waswashed with EtOAc (3 X 50 mL). The combined filtrates were concentratedin vacuo. The residue was chromatographed (SiO₂; continuous gradientfrom 0% to 100% EtOAc in hexanes over 20 min) to give the title compoundas a white solid (16.6 g, 74% yield). ¹H NMR (400 MHz, CD₃OD) δ 8.60 (d,J=2.2 Hz, 1H), 7.99 (dd, J=8.4, 2.2 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H),4.41 (s, 2H).

5B. (5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol

To a degassed (sparged with Ar 3X) solution of 5A (1.9 g, 8.40 mmol) indioxane (42.0 mL) was addedchloro(pentamethylcyclopentadienyl)bis(triphenylphosphine)ruthenium (II)(0.402 g, 0.504 mmol). The mixture was degassed under Ar (3X), afterwhich TMSCH₂N₃ (1.87 mL, 12.6 mmol) was added. The reaction was stirredat 50° C. for 15 h under Ar, then was cooled to RT and concentrated invacuo. The oily crude product was dissolved in THF (90 mL) and cooled to0° C. TBAF (5.40 mL of a 1.0 M solution in THF; 5.40 mmol) was added andthe reaction was stirred at 0° C. for 10 min, after which solid NaHCO₃(4 g) was added. The reaction mixture was stirred for 30 min at RT andthen filtered. The filtrate was concentrated in vacuo. The residue waschromatographed (SiO₂; continuous gradient from 0% to 100% EtOAc inhexanes, 20 min) to give the title compound (1.30 g, 4.59 mmol, 102%yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 8.49 (dd, J=2.3, 0.7Hz, 1H), 8.08 (dd, J=8.5, 0.6 Hz, 1H), 7.83 (dd, J=8.5, 2.2 Hz, 1H),6.16 (t, J=6.9 Hz, 1H), 4.68 (d, J=6.9 Hz, 2H), 3.95 (s, 3H).

5C. 5-Bromo-2-(5-(bromomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridine

To a stirred solution of Example 5B (300 mg, 1.15 mmol) in dry CH₂Cl₂ (8mL) was added PBr₃ (0.21 mL, 2.23 mmol) and the resulting solution wasstirred at 0° C. for 45 min. The reaction mixture was then quenched withwater (20 mL), extracted with EtOAc (2 x 20 mL) and the combined organicextracts were washed with brine (25 mL), dried (Na₂SO₄) and concentratedin vacuo to afford the title compound (250 mg, 67%) as a yellow oilyliquid. LCMS, [M + H]⁺ = 329.9. ¹HNMR (300 MHz, CDCl₃) δ 8.64 (d, J =2.10 Hz, 1H), 8.14 (dd, J = 0.90, 8.56 Hz, 1H), 7.90 (dd, J = 2.40, 5.70Hz, 1H), 5.18 (s, 2H), 4.13 (s, 3H).

5D. 2-(Azidomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-5-bromopyridine

To a solution of Example 5C (220 mg, 0.66 mmol) in dry DMF (2.5 mL) wasadded NaN₃ (86 mg, 1.33 mmol) and the resulting solution was stirred at70° C. for 16 h, then was cooled to RT and poured into water (25 mL).The precipitated solid product was filtered, washed with water (5 mL)and dried in vacuo to afford the title compound (162 mg, 82%) as a whitesolid. LCMS, [M + H]⁺ = 296.0. ¹H NMR (400 MHz, DMSO-d6) δ 8.76 (dd, J=0.8, 2.4 Hz, 1H), 8.18 (dd, J = 2.4, 8.4 Hz, 1H), 8.06 (dd, J = 0.8, 8.6Hz, 1H), 5.10 (s, 2H), 4.11 (s, 3H).

5E. tert-Butyl((4-(5-bromopyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)carbamate

To a solution of Example 5D (100 mg, 0.34 mmol) in THF (3 mL) under N₂was added Ph₃P (178 mg, 0.680 mmol) and water (1 mL) and the resultingsolution was stirred at RT for 16 h. To this reaction mixture was addedNaOH (34 mg, 0.85 mmol) followed by (Boc)₂O (0.10 mL, 0.48 mmol) and thereaction was stirred at RT for another 16 h. The reaction mixture wasdiluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). Thecombined organic extracts were washed with brine (25 mL), dried(Na₂SO₄), and concentrated in vacuo to afford the title compound (100mg, 80%) as a white solid. LCMS, [M + H]⁺ = 368.2. ¹H NMR (300 MHz,CDCl₃) δ 8.67 (d, J= 2.1 Hz, 1H), 8.15 (d, J= 8.7 Hz, 1H), 7.92 (dd, J =2.4, 8.4 Hz, 1H), 5.98-5.99 (m, 1H), 4.60 (d, J= 6.0 Hz, 2H), 4.21 (s,3H), 1.41 (s, 9H).

5F. tert-Butyl((1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-1H-1,2,3-triazol-5-yl)methyl)carbamate

To a solution of Example 5E (50 mg, 0.136 mmol) in dioxane (5 mL) wasadded bis(pinacolato)diboron (51.7 mg, 0.204 mmol) and KOAc (27 mg, 0.27mmol). The reaction mixture was purged with N₂ for 5 min, after which1,1′-bis(diphenyl-phosphino)ferrocenepalladium(II) dichloride DCMcomplex (6 mg, 0.006 mmol) was added. The reaction mixture was stirredat 90° C. for 16 h, then was cooled to RT. The mixture was filtered andthe filtrate was concentrated in vacuo to afford the crude titlecompound (70 mg) as a brown liquid. LCMS: [M + H]⁺ = 416.0. This crudeproduct was used in the next reaction without further purification.

5G. tert-Butyl((4-(5-hydroxypyridin-2-yl)-1-methyl-1H-1,2,3-triazol-5-yl)methyl)carbamate

To a stirred solution of Example 5F (70 mg, 0.722 mmol), in THF (5 mL)and water (1.5 mL) was added sodium perborate monohydrate (41 mg, 0.407mmol). The reaction mixture was stirred at RT for 1 h, then was dilutedwith water (20 mL). This mixture was extracted 1.with 10% MeOH in CHCl₃(2 x 10 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated in vacuo. The crude product was chromatographed (12 gRedisep® SiO₂ column, eluting with 3% MeOH in CHCl₃) to afford the titlecompound (40 mg, 96%) as a pale yellow liquid. LCMS, [M + H]⁺ = 306.2.This crude material was used without further purification in the nextreaction.

5H. (1S,3S)-Ethyl3-((6-(5-(((tert-butoxycarbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate

To a solution of Example 5G (1.80 g, 5.90 mmol) in THF (35 mL) weresuccessively added di-tert-butyl azodicarboxylate (4.07 g, 17.7 mmol),Ph₃P (4.64 g, 17.7 mmol) and (1S, 3R)-ethyl 3-hydroxycyclohexanecarboxylate (synthesized according to the analogous proceduredescribed in US2007/0197788A1, 1.52 g, 8.84 mmol) under N₂. The reactionsolution was stirred at 60° C. for 16 h, then was cooled to RT andconcentrated in vacuo. The crude product was chromatographed (24 g SiO₂,40% EtOAc in hexanes) to afford the title compound (1.9 g, 70%) as apale yellow solid. LCMS, [M + H]⁺ = 460.1. ¹HNMR (300 MHz, CDCl₃) δ 8.30(d, J = 2.1 Hz, 1H), 8.15 (d, J= 5.4 Hz, 1H), 7.34 (dd, J= 2.4, 6.5 Hz,1H), 6.13 (s, 1H), 4.71 (s, 1H), 4.58 (d, J = 1.5 Hz, 2H), 4.20 (s, 3H),4.12 (q, J = 3.0 Hz, 2H), 2.80-2.82 (m, 1H), 2.02-2.05 (m, 1H),1.84-1.99 (m, 3H), 1.56-1.79 (m, 4H), 1.41 (s, 9H), 1.26 (t, J= 1.2 Hz,3H).

5I. (1S,3S)-Ethyl3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate

To a stirred solution of Example 5H (1.90 g, 4.13 mmol) in CH₂Cl₂ (50mL) was added HCl in dioxane (10.3 mL of a 4 M solution, 41.3 mmol) andthe resulting solution was stirred at RT for 12 h. The reaction mixturewas concentrated in vacuo to afford the title compound (1.25 g, 84%) asa pale yellow solid. LCMS, [M + H]⁺ = 360.0. This crude product was usedwithout further purification in the next reaction.

5J Ethyl(1S,3S)-3-((6-(5-(((butoxycarbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a stirred solution of Example 5I (30 mg, 0.083 mmol) in CH₂Cl₂ (5 mL)under N₂ was added n-butyl chloroformate (78 µL, 0.83 mmol), and theresulting solution was stirred at RT for 16 h. The reaction mixture wasconcentrated in vacuo and the crude product was chromatographed (12 gSiO₂, isocratic 27% EtOAc in hexanes) to afford the title compound (30mg, 82%) as a pale yellow liquid. LCMS, [M + H]⁺ = 432.2.

Example 5

To a stirred solution of Example 5J (30 mg, 0.046 mmol) in THF (4 mL)and MeOH (1 mL) was added a solution of LiOH.H₂O (2 mg, 0.093 mmol) inwater (1.5 mL) and the resulting solution was stirred at RT for 16 h.The reaction mixture was diluted with water (20 mL) and washed with Et₂O(20 mL). The aqueous layer was neutralized with aq. 1.5 N HCl (2 mL) andextracted with 5% MeOH in CHCl₃ (25 mL). The organic layer was washedwith brine (25 mL), dried (Na₂SO₄) and concentrated in vacuo. The crudeproduct was purified by preparative reverse phase HPLC (Sunfire C18 (150x19) mm; 5 µm; mobile phase A: 10 mM aq. NH₄OAc (pH: 4.5); mobile phaseB: MeCN, flow rate: 15 mL/min; time (min)/%B: 0/20, 25/60; retentiontime: 15.19 min) to afford the title compound (6 mg, 32%) as a whitesolid. LCMS, [M + H]⁺ = 432.0. ¹H NMR (400 MHz, CD₃OD) δ 8.40 (br. s., 1H) 8.00 (d, J=8.8 Hz, 1 H) 7.53 (dd, J=8.8, 2.7 Hz, 1 H), 4.70-4.80 (m,1 H) 4.58 (s, 3 H) 4.20 (s, 3 H) 4.03 (t, J=6.6 Hz, 2 H) 2.77 - 2.88 (m,1 H) 1.87 - 2.15 (m, 3 H) 1.45 - 1.86 (m, 6 H) 1.23 - 1.44 (m, 2 H) 0.92(t, J=7.3 Hz, 3 H). hLPA₁ IC₅₀ = 96 nM.

Table 1 below lists additional Examples which were made via the samesynthetic method described herein.

TABLE 1 Ex # Structure & Name Analytical & Biology Data Method 6

LCMS, [M + H]⁺ = 444.2; ¹H NMR (400 MHz, CD₃OD): δ 8.38 (s, 1H), 7.97(d, J = 7.20 Hz, 1H), 7.51 (d, J = 8.80 Hz, 1H), 5.02-5.06 (m, 1H),4.72-4.78 (m, 3H), 4.17 (s, 3H), 2.72-2.78 (m, 1H), 2.01-2.09 (m, 1H),1.90-1.98 (m, 3H), 1.52-1.78 (m, 13H); hLPA₁ IC₅₀ = 84 nM. Example 3

7

LCMS, [M + H]⁺ = 444.2; ¹H NMR (400 MHz, CD30D): δ 7.85 (d, J = 8.40 Hz,1H), 7.47 (d, J = 8.80 Hz, 2H), 4.72-4.78 (m, 1H), 4.57 (s, 2H), 4.19(s, 3H), 3.88 (d, J = 7.20 Hz, 2H), 2.79-2.81 (m, 1H), 2.56 (s, 3H),1.97-2.11 (m, 1H), 1.79-1.97 (m, 3H), 1.65-1.72 (m, 4H), 0.50-0.55 (m,2H), 0.26 (d, J = 4.80 Hz, 2H); hLPA₁ IC₅₀ = 47 nM. Example 3 8

LCMS, [M + H]⁺ = 516.1; ¹H NMR (400 MHz, CD30D): δ 7.84 (d, J = 8.80 Hz,1H), 7.59 (d, J = 8.80 Hz, 2H), 4.99 (s, 2H), 4.65 (s, 2H), 4.06 (s,3H), 2.63-2.72 (m, 1H), 2.49 (s, 3H), 1.97-2.07 (m, 1H), 1.79-1.97 (m,3H), 1.54-1.72 (m, 4H); hLPA₁ IC₅₀ = 5 nM. Example 1 9

LCMS, [M + H]⁺ = 480.0; ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (d, J=2.93 Hz,1 H) 7.98 (d, J=8.80 Hz, 1 H) 7.50 - 7.54 (m, 1 H) 7.18 -7.29 (m, 5 H)4.78 - 4.80 (m, 1 H) 4.73 (d, J=5.38 Hz, 2 H) 4.10 - 4.16 (m, 2 H) 4.03(s, 3 H) 2.78 - 2.87 (m, 2 H) 2.64 - 2.68 (m, 1 H) 1.95 (s, 1 H) 1.83(br. S., 4 H) 1.51 - 1.68 (m, 3 H); hLPA₁ IC₅₀ = 672 nM. Example 1 10

LCMS, [M + H]⁺ = 480.2; ¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (d, J=3.18 Hz,1 H) 7.97 (d, J=8.80 Hz, 1 H) 7.49 - 7.66 (m, 2 H) 7.32 (br. s., 4 H)5.67 (d, J=6.60 Hz, 1 H) 4.76 (br. s., 1 H) 4.76 (br. s., 2 H) 4.02 (s,3 H) 2.68 (br. s., 1 H) 1.74 - 1.93 (m, 4 H) 1.50 - 1.68 (m, 4 H) 1.42(d, J=6.60 Hz, 3 H); hLPA₁ IC₅₀ = 104 nM. Example 1 11

LCMS, [M + H]⁺ = 498.1; ¹H NMR (400 MHz, CD30D): δ 7.84 (d, J = 8.00 Hz,1H), 7.45 (d, J = 8.40 Hz, 1H), 7.32-7.37 (m, 1H), 7.01-7.15 (m, 3H),5.10 (s, 2H), 4.74-7.79 (m, 3H), 4.16 (s, 3H), 2.78-2.84 (m, 1H), 2.52(s, 3H), 2.10-2.14 (m, 1H), 1.92-1.98 (m, 3H), 1.63-1.78 (m, 4H); hLPA₁IC₅₀ = 6 nM. Example 1 12

LCMS, [M + H]⁺ = 484.2; ¹H NMR (400 MHz, CD30D): δ 7.99 (d, J = 7.60 Hz,1H), 7.52 (d, J = 8.00 Hz, 1H), 7.32-7.37 (m, 1H), 7.01-7.14 (m, 3H),5.08 (s, 2H), 4.74-4.79 (m, 3H), 4.19 (s, 3H), 2.81-2.84 (m, 1H),2.01-2.11 (m, 1H), 1.90-2.00 (m, 3H), 1.62-1.79 (m, 4H); hLPA₁ IC₅₀ = 23nM. Example 1 13

LCMS, [M + H]⁺ = 460.2; ¹H NMR (400 MHz, CD₃OD) δ 8.40 (d, J=3.0 Hz, 1H) 8.00 (d, J=8.5 Hz, 1 H) 7.53 (dd, J=8.9, 2.8 Hz, 1 H) 4.75 (s, 1 H)4.73(m 2H) 4.20 (s, 3 H) 4.02 (t, J=6.5 Hz, 2 H) 2.82 (d, J=4.5 Hz, 1 H)2.08 (br. s., 1 H) 1.93 (br. s., 3 H) 1.66 -1.77 (m, 6H) 1.31 (d, J=3.5Hz, 6 H) 0.90 (s, 3 H); hLPA₁ IC₅₀ = 428 nM. Example 3 14

LCMS, [M + H]⁺ = 446.2; ¹H NMR (400 MHz, CD₃OD) δ 8.37 (br. s., 1 H)7.98 (d, J=9.04 Hz, 1 H) 7.48 - 7.56 (m, 1 H) 5.19 (s, 2 H), 4.92 (m,2H), 4.80 (m 1H) 4.07 - 4.17 (m, 3 H), 2.82 (s, 3 H), 2.05 (d, J=13.05Hz, 2 H), 1.60 -1.81 (m, 8 H), 1.32 - 1.45 (m, 2 H), 1.41 (br. s., 1 H),0.88 - 1.01 (m, 3 H); hLPA₁ IC₅₀ = 1024 nM. Example 2 15

LCMS, [M + H]⁺ = 460.4; ¹H NMR (400 MHz, CD₃OD) δ 8.37 (d, J=3.01 Hz, 1H) 7.98 (d, J=9.04 Hz, 1 H) 7.53 (dd, J=9.04, 3.01 Hz, 1 H) 5.19 (s, 2H)4.9(m 2 H) 4.7(m 1H) 4.05 - 4.16 (m, 3 H) 2.82 (s, 3 H) 2.07 (br. s.,3 H) 1.92 (br. s., 2 H) 1.57 - 1.82 (m, 6 H) 1.25 -1.44 (m, 5 H) 0.83 -1.00 (m, 3 H); hLPA₁ IC₅₀ = 130 nM. Example 2 16

LCMS, [M + H]⁺ = 494.1; 1H NMR (400 MHz, CD30D): δ 7.83 (d, J = 8.80 Hz,1H), 7.45 (d, J = 8.40 Hz, 1H), 7.13-7.17 (m, 5H), 4.77-4.77 (m, 1H),4.69 (s, 2H), 4.24 (t, J = 6.80 Hz, 2H), 4.15 (s, 3H), 2.79-2.88 (m,3H), 2.50 (s, 3H), 2.09-2.17 (m, 1H), 1.89-1.97 (m, Example 1

3H), 1.55-1.78 (m, 4H); hLPA₁ IC₅₀ = 32 nM. 17

LCMS, [M + H]⁺ = 516.1; ¹H NMR (400 MHz, CD30D): δ 7.84 (d, J = 8.80 Hz,1H), 7.46 (d, J = 8.80 Hz, 2H), 5.14 (s, 2H), 4.72-4.84 (m, 3H), 4.17(s, 3H), 2.76-2.82 (m, 1H), 2.52 (s, 3H), 1.97-2.11 (m, 1H), 1.79-1.97(m, 3H), 1.65-1.72 (m, 4H); hLPA₁ IC₅₀ = 7 nM. Example 1 18

LCMS, [M + H]⁺ = 494.1; ¹H NMR (400 MHz, CD30D): δ 7.71 (d, J = 8.40 Hz,1H), 7.34 (d, J = 8.80 Hz, 1H), 7.14-7.18 (m, 5H), 5.59-5.63 (m, 1H),4.63-4.74 (m, 3H), (s, 2H), 3.97 (s, 3H), 2.69-2.70 (m, 1H), 2.44 (s,3H), 1.97-2.09 (m, 1H), 1.81-1.97 (m, 4H), 1.50-1.78 (m, 7H), 1.32-1.36(m, 3H); hLPA₁ IC₅₀ = 12 nM. Example 1 19

LCMS, [M + H]⁺ = 494.1; ¹H NMR (400 MHz, CD30D): δ 7.82 (d, J = 8.00 Hz,1H), 7.44 (d, J = 8.40 Hz, 1H), 4.77-7.48 (m, 3H), 5.03 (s, 2H), 4.14(s, 3H), 2.76-2.81 (m, 1H), 2.50 (s, 3H), 2.30 (s, 3H), 1.97-2.09 (m,1H), 1.81-1.97 (m, 3H), 1.59-1.78 (m, 4H); hLPA₁ IC₅₀ = 4 nM. Example 120

LCMS, [M + H]⁺ = 474.1; ¹H NMR (400 MHz, CD30D): δ 7.83 (d, J = 8.40 Hz,1H), 7.45 (d, J = 8.80 Hz, 1H), 4.77-4.79 (m, 1H), 4.76 (s, 2H), 4.16(s, 3H), 4.02 (t, J = 6.80 Hz, 2H), 2.80-2.82 (m, 1H), 2.52 (s, 3H),2.09-2.17 (m, 1H), 1.89-1.97 (m, 3H), 1.55-1.78 (m, 6H), 1.21-1.29 (m,6H), 0.84 (t, J = 2.00 Hz, 3H); hLPA₁ IC₅₀ = 3 nM. Example 3 21

LCMS, [M + H]⁺ = 448.1; ¹H NMR (400 MHz, DMSO-d6): δ 7.83 (d, J = 8.40Hz, 1H), 7.61-7.64 (m, 1H), 7.48 (d, J = 9.60 Hz, 1H), 4.76-4.78 (m,3H), 4.05-4.08 (m, 5H), 3.45-3.53 (m, 2H), 3.2 (s, 3H), 2.59-2.62 (m,1H), 2.44 (s, 3H), 1.99-2.05 (m, 1H), 1.75-1.90 (m, 3H), 1.48-1.63 (m,4H); hLPA₁ IC₅₀ = 1615 nM. Example 3 22

LCMS, [M + H]⁺ = 460.1; ¹H NMR (400 MHz, CD30D): δ 7.85 (d, J = 8.40 Hz,1H), 7.47 (d, J = 8.40 Hz, 1H), 4.77-4.79 (m, 1H), 4.76 (s, 2H), 4.18(s, 3H), 3.76 (s, 2H), 2.80-2.82 (m, 1H), 2.55 (s, 3H), 2.10-2.17 (m,1H), 1.89-1.97 (m, 3H), 1.62-1.78 (m, 4H), 0.90 (s, 9H); hLPA₁ IC₅₀ = 35nM. Example 3 23

LCMS, [M + H]⁺ = 460.4; ¹H NMR (400 MHz, CD30D): δ 7.83 (d, J = 8.80 Hz,1H), 7.45 (d, J = 8.80 Hz, 1H), 4.77-4.79 (m, 1H), 4.74 (s, 2H), 4.16(s, 3H), 4.02 (t, J = 7.60 Hz, 2H), 2.80-2.82 (m, 1H), 2.53 (s, 3H),2.09-2.17 (m, 1H), Example 3

1.89-1.97 (m, 3H), 1.55-1.78 (m, 6H), 1.23-1.31 (m, 4H), 0.88 (t, J =7.20 Hz, 3H); hLPA₁ IC₅₀ = 3 nM. 24

LCMS, [M + H]⁺ = 432.1; ¹H NMR (400 MHz, CD₃OD): 400 MHz, MeOD: δ 7.83(d, J = 8.80 Hz, 1H), 7.45 (d, J = 8.80 Hz, 1H), 4.77-4.79 (m, 1H), 4.74(s, 2H), 4.16 (s, 3H), 3.98 (t, J = 6.40 Hz, 2H), 2.80-2.82 (m, 1H),2.53 (s, 3H), 2.09-2.17 (m, 1H), 1.89-1.97 (m, 3H), 1.55-1.78 (m, 6H),0.90 (t, J = 7.20 Hz, 3H); hLPA₁ IC₅₀ = 160 nM. Example 3 25

LCMS, [M + H]⁺ = 446.0; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (d, J=7.9 Hz,1H), 7.48 (d, J=8.5 Hz, 1H), 4.90 - 4.64 (m, 3H), 4.04 (s, 3H), 3.56 (d,J=14.0 Hz, 2H), 2.44 (br. s., 3H), 2.07 - 1.39 (m, 10H), 0.82 (br. s.,6H); hLPA₁ IC₅₀ = 51 nM. Example 3 26

LCMS, [M + H]⁺ = 446.1; ¹H NMR (400 MHz, CD₃OD) δ 8.40 (br. S., 1 H)7.99 (d, J=9.05 Hz, 1 H) 7.53 (dd, J=8.80, 2.93 Hz, 1 H) 4.76 (br. S., 1H) 4.19 (s, 3 H) 3.75 (s, 2 H) 2.77 -2.89 (m, 1 H) 1.87 - 2.17 (m, 4 H)1.58 - 1.85 (m, 4 H) 0.90 (s, 9 H); hLPA₁ IC₅₀ = 44 nM. Example 3 27

LCMS, [M + H]⁺ = 446.1; ¹H NMR (400 MHz, CD₃OD) δ 8.40 (br. S., 1 H),8.00 (d, J=8.80 Hz, 1 H), 7.53 (dd, J=8.80, 2.69 Hz, 1 H), 4.74 (br. S,3H), 4.20 (s, 3 H), 4.02 (t, J=6.60 Hz, 2 H), 2.77 - 2.88 (m, 1 H),1.87 - 2.15 (m, 4 H), 1.44 -1.85 (m, 6 H), 1.31 (br. S., 4 H), 0.92 (t,J=7.34 Hz, 3 H); hLPA₁ IC₅₀ = 16 nM. Example 3 28

LCMS, [M + H]⁺= 458.2; ¹H NMR (400 MHz, CD₃OD): δ 7.82 (d, J = 8.40 Hz,1H), 7.45 (d, J = 8.80 Hz, 1H), 5.02-5.05 (m, 1H), 4.73-4.77 (m, 1H),4.56 (s, 2H), 4.15 (s, 3H), 2.72-2.77 (m, 1H), 2.53 (s, 3H), 2.30-2.18(m, 1H), 1.91-1.98 (m, 3H), 1.52-1.78 (m, 12H); hLPA₁ IC₅₀ = 18 nM.Example 3 29

LCMS, [M + H]⁺ = 432.2; 1H NMR (400 MHz, CD₃OD): δ 8.38 (s, 1H), 7.98(d, J = 8.00 Hz, 1H), 7.51 (dd, J = 2.40, 8.80 Hz, 1H), 4.78-4.79 (m,1H), 4.72 (s, 2H), 4.17 (s, 3H), 3.79 (d, J = 6.80 Hz, 2H), 2.75-2.79(m, 1H), 2.01-2.06 (m, 1H), 1.87-2.00 (m, 3H), 1.61-1.78 (m, 5H), 0.88(d, J = 6.40 Hz, 6H); hLPA₁ IC₅₀ = 179 nM. Example 3 30

LCMS, [M + H]⁺ = 446.4; ¹H NMR (400 MHz, CD₃OD): δ 7.83 (d, J = 8.80 Hz,1H), 7.45 (d, J = 8.40 Hz, 1H), 4.79-4.81 (m, 1H), 4.68 (s, 2H),2.76-2.79 (m, 1H), 2.09-2.12 (m, 1H), 1.91-1.98 (m, 3H), 1.63-1.78 (m,4H), 1.41 (s, 9H); hLPA₁ IC₅₀ = 120 nM. Example 3 31

LCMS, [M + H]⁺ = 500.3; ¹H NMR (500 MHz, DMSO-d₆) δ 8.35 (br s, 1H),7.97 (br d, J=8.7 Hz, 1H), 7.63 - 7.50 (m, 2H), 4.87 - 4.70 (m, 3H),4.05 (s, 3H), 3.83 (br d, J=5.1 Hz, 2H), 2.70 - 2.61 (m, 1H), 2.39 -1.43 (m, 11H), 0.94 (br d, J=5.1 Hz, 3H); hLPA₁ IC₅₀ = 102 nM. Example 132

LCMS, [M + H]⁺ = 514.1; ¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=8.8 Hz,1H), 7.69 (br d, J=8.1 Hz, 1H), 4.86 - 4.77 (m, 1H), 4.60 (s, 2H), 4.20(s, 3H), 4.02 - 3.92 (m, 2H), 2.68 (s, 3H), 2.30 -1.62 (m, 11H), 1.06(d, J=6.6 Hz, 3H); hLPA₁ IC₅₀ = 69 nM Example 1 33

LCMS, [M + H]⁺ = 458.0; ¹H NMR (500 MHz, DMSO-d₆) □ 7.81 (d, J=8.4 Hz,1H), 7.58 (br. s., 1H), 7.47 (d, J=8.5 Hz, 1H), 4.81 -4.67 (m, 3H), 4.03(s, 3H), 3.94 - 3.85 (m, 2H), 2.66 -2.56 (m, 1H), 2.47 - 2.37 (m, 4H),2.03 - 1.41 (m, 14H); hLPA₁ IC₅₀ = 11 nM. Example 3 34

LCMS, [M - H]⁺ = 480.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.81 (d, J=8.3 Hz,1H), 7.68 (br. s., 1H), 7.47 (d, J=8.4 Hz, 1H), 7.30 (br. s., 5H), 5.01(br. s., 2H), 4.82 - 4.70 (m, 3H), 4.03 (br. s., 3H), 2.61 - 2.55 (m,1H), 2.41 (s, 3H), 2.02 - 1.45 (m, 8H); hLPA₁ IC₅₀ = 9 nM, acute in vivohistamine assay in CD-1 mice : -96% histamine at a 1 mg/kg dose ofExample 34. Example 3 35

LCMS, [M + H]⁺ = 494.0; ¹H NMR (500 MHz, DMSO-d₆) δ 7.86 - 7.69 (m, 1H),7.52 - 7.26 (m, 6H), 5.20 -5.06 (m, 4H), 4.81 - 4.70 (m, 1H), 3.97 (br.s., 3H), 3.32 (br. s., 3H), 2.66 - 2.59 (m, 1H), 2.40 (br. s., 3H), 2.05-1.41 (m, 8H); hLPA₁ IC₅₀ = 56 nM. Example 2 36

LCMS, [M + H]⁺ = 457.9; ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J=7.9 Hz,1H), 7.48 (d, J=8.2 Hz, 1H), 5.11 (br. s., 2H), 4.81 - 4.71 (m, 1H),3.99 (s, 5H), 2.66 -2.56 (m, 1H), 2.73 (s, 3H), 2.42 (s, 3H), 2.03 -1.20 (m, 12H), 0.93 - 0.80 (m, 3H); hLPA₁ IC₅₀ = 19 nM. Example 2 37

LCMS, [M + H]⁺ = 474.0; ¹H NMR (500 MHz, DMSO-d₆) δ 7.81 (d, J=8.1 Hz,1H), 7.54 - 7.39 (m, 2H), 4.80 -4.65 (m, 3H), 4.09 - 3.90 (m, 5H),2.60 - 2.55 (m, 1H), 2.42 (s, 3H), 2.01 - 1.35 (m, 10H), 0.83 (br. s.,9H); hLPA₁ IC₅₀ = 12 nM. Example 3 38

LCMS, [M + H]⁺ = 486.0; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (d, J=8.4 Hz,1H), 7.55 (br. s., 1H), 7.47 (d, J=8.6 Hz, 1H), 4.82 - 4.67 (m, 3H),4.03 (s, 3H), 3.89 (d, J=4.3 Hz, 1H), 2.67 -2.57 (m, 1H), 2.46 - 2.32(m, 4H), 2.04 - 1.38 (m, 13H), 1.07 (br. s., 3H), 0.96 (br. s., 3H);hLPA₁ IC₅₀ = 19 nM. Example 3 39

LCMS, [M + H]⁺ = 443.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.79 (br. s., 1H),7.64 (d, J=7.3 Hz, 2H), 7.03 (d, J=8.2 Hz, 2H), 4.71 - 4.63 (m, 1H),4.41 (d, J=4.6 Hz, 2H), 4.08 - 3.94 (m, 5H), 2.67 - 2.56 (m, 1H), 1.94-1.37 (m, 10H), 0.74 - 0.60 (m, 1H), 0.44 - 0.32 (m, 2H), 0.09 - -0.01(m, 2H); hLPA₁ IC₅₀ = 457 nM. Example 4 40

LCMS, [M + H]⁺= 465.0; ¹H NMR (500 MHz, DMSO-d₆) δ 8.04 - 7.92 (m, 1H),7.65 (br d, J=8.2 Hz, 2H), 7.41 - 7.29 (m, 5H), 7.03 (br d, J=7.9 Hz,2H), 5.06 (s, 2H), 4.75 - 4.63 (m, 1H), 4.46 (br d, J=4.9 Hz, 2H), 4.04(s, 3H), 2.72 - 2.63 (m, 1H), 2.02 - 1.47 (m, 8H); hLPA1 IC₅₀ = 664 nM.Example 4 41

LCMS, [M + H]⁺= 460.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (br d, J=8.5 Hz,1H), 7.45 (br d, J=8.9 Hz, 2H), 4.75 (br s, 3H), 4.02 (s, 3H), 3.91 (brs, 1H), 3.64 (br d, J=15.9 Hz, 2H), 2.81 (q, J=7.3 Hz, 2H), 2.04 - 1.97(m, 1H), 1.84 (br d, J=12.8 Hz, 1H), 1.81 - 1.73 (m, 2H), 1.63 - 1.50(m, 3H), 1.45 (br s, 3H), 1.28 - 1.18 (m, 6H), 0.81 (br s, 3H); hLPA₁IC₅₀ = 8 nM. Example 1 42

LCMS, [M + H]⁺ = 446.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.80 (br d, J=8.2Hz, 1H), 7.44 (br d, J=8.5 Hz, 1H), 4.73 (br d, J=18.6 Hz, 2H), 4.02 (s,2H), 3.96 - 3.75 (m, 10H), 2.80 (q, J=7.3 Hz, 1H), 1.99 (br d, J=16.2Hz, 1H), 1.83 (br d, J= 12.2 Hz, Example 1

1H), 1.80 - 1.70 (m, 1H), 1.62 - 1.50 (m, 2H), 1.46 (br s, 2H), 1.26 -1.15 (m, 3H), 0.78 (br s, 2H); hLPA₁ IC₅₀ = 788 nM. 43

LCMS, [M + H]⁺ = 494.4; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (br d, J=8.2Hz, 1H), 7.46 (br d, J=8.5 Hz, 1H), 7.34 - 7.27 (m, 5H), 5.00 (br s,2H), 4.81 (br s, 2H), 4.76 (br s, 1H), 4.02 (br s, 3H), 3.56 (br s, 1H),2.80 (br d, J=7.3 Hz, 2H), 2.63 -2.57 (m, 1H), 2.05 - 1.98 (m, 1H), 1.85(br d, J=12.8 Hz, 1H), 1.81 - 1.74 (m, 2H), 1.63 - 1.52 (m, 3H), 1.48(br d, J=7.6 Hz, 1H), 1.21 (br t, J=7.2 Hz, 3H); hLPA₁ IC₅₀ = 8 nM.Example 1 44

LCMS, [M + H]⁺ = 472.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J=8.5Hz, 1H), 7.48 (d, J=8.9 Hz, 1H), 4.94 (br s, 1H), 4.77 (br s, 3H), 4.04(s, 3H), 2.91 - 2.73 (m, 2H), 2.61 (br t, J=10.5 Hz, 1H), 2.08 - 1.95(m, 1H), 1.86 (br d, J=12.2 Hz, 1H), 1.83 - 1.71 (m, 3H), 1.62 (br d,J=9.5 Hz, 3H), 1.55 (br s, 3H), 1.51 (br s, 4H), 1.25 (br t, J=7.3 Hz,4H); hLPA₁ IC₅₀ = 37 nM. Example 1 45

LCMS, [M + H]⁺= 474.4; ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J=8.2 Hz,1H), 7.49 (br d, J=8.2 Hz, 2H), 4.77 (br s, 3H), 4.04 (s, 3H), 3.65 (brs, 2H), 2.90 -2.71 (m, 2H), 2.60 (br s, 1H), 2.01 (br d, J=11.9 Hz, 1H),1.90 (s, 1H), 1.87 - 1.72 (m, 3H), 1.67 - 1.53 (m, 3H), 1.50 (br s, 1H),1.25 (br t, J=7.5 Hz, 3H), 0.83 (br s, 9H); hLPA₁ IC₅₀ = 94 nM. Example1 46

LCMS, [M + H]⁺= 460.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br s, 1H), 7.49(br d, J=8.5 Hz, 1H), 4.78 (br s, 3H), 4.04 (s, 3H), 3.73 (br d, J=6.1Hz, 1H), 2.83 (br d, J=7.3 Hz, 2H), 2.61 (br t, J=10.4 Hz, 1H), 2.09 -1.97 (m, 1H), 1.86 (br d, J=12.5 Hz, 1H), 1.83 - 1.72 (m, 3H), 1.66 -1.46 (m, 5H), 1.25 (br t, J=7.2 Hz, 4H), 0.83 (br d, J=5.8 Hz, 6H);hLPA₁ IC₅₀ = 120 nM. Example 1

Table 2 below lists additional Examples which were synthesized via theintermediates described as follows.

Intermediate 2 4-Nitrophenyl ((1-propylcyclopropyl)methyl) Carbonate

Intermediate 2A. Tert-butyl 1-propylcyclopropane-1-carboxylate

To a solution of LDA in THF (40 mL of a 0.8 M solution; 33.2 mmol) at-78° C. was added tert-butyl cyclopropane carboxylate (3.78 g, 26.6mmol) dropwise over 10 min. The solution was stirred at -78° C. for 2 h,after which 1-bromopropane (4.84 mL, 53.2 mmol) was added dropwise over20 min at -78°. The reaction was allowed to slowly warm to RT andstirred overnight at RT, then was quenched with sat’d aq. NH₄Cl andextracted with EtOAc (2x). The combined organic extracts were washedwith brine, dried (MgSO₄), and concentrated in vacuo. The residue wasdistilled under reduced pressure (20 torr, BP = 95° C.) to give thetitle compound (2.99 g, 61% yield) as an oil. ¹H NMR (500 MHz, CDCl₃) δ1.48 (m, 4H), 1.45 (s, 9H), 1.12 (m, 2H), 0.92 (m, 3H), 0.61 (m, 2H).

Intermediate 2B. (1-propylcyclopropyl)methanol

To a solution of Intermediate 2A (250 mg, 1.36 mmol) in Et₂O (5 mL) wasadded LiAlH₄ (103 mg, 2.71 mmol) portionwise at RT; the reaction wasstirred overnight at RT. The mixture was sequentially treated with water(0.1 mL), 15% aq. NaOH (0.1 mL), and water (0.3 mL), then was stirred atRT for 1 h, dried (MgSO₄) and concentrated in vacuo. The residue wasdistilled under reduced pressure to give the slightly impure titlecompound (186 mg) as an oil. ¹H NMR (500 MHz, CDCl₃) δ 3.44 (br s, 2H),1.48 - 1.36 (m, 4H), 0.93 (t, J=7.0 Hz, 3H), 0.44 - 0.27 (m, 4H).

Intermediate 2

To a RT solution of Intermediate 2B (155 mg, 1.36 mmol) in CH₂Cl₂ (10mL) was added pyridine (0.44 mL, 5.43 mmol) and 4-nitrophenylchloroformate (410 mg, 2.04 mmol). After stirring for 2 h at RT, thereaction mixture was concentrated in vacuo and the residue waschromatographed (SiO₂; continuous gradient from 0-25% EtOAc in Hexanes)to give the title compound Intermediate 2 (226 mg, 60% yield) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ 8.31 (d, J=9.1 Hz, 2H), 7.42 (d, J=9.1Hz, 2H), 4.15 (s, 2H), 1.45 (m, 4H), 0.96 (t, J=7.0 Hz, 3H), 0.58 (m,2H), 0.51 (m, 2H).

The following intermediates were prepared using the same syntheticsequence as for Intermediate 2 starting from either tert-butylcyclopropanecarboxylate or tert-butyl cyclobutanecarboxylate and thenalkylating with the required alkyl iodide or bromide.

Intermediate 3. (1-methylcyclopropyl)methyl (4-nitrophenyl) Carbonate

¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, J=9.2 Hz, 2H), 7.40 (d, J=9.2 Hz,2H), 4.10 (s, 2H), 1.22 (s, 3H), 0.60 (m, 2H), 0.47 (m, 2H).

Intermediate 4. (1-ethylcyclopropyl)methyl (4-nitrophenyl) Carbonate

¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, J=9.2 Hz, 2H), 7.39 (d, J=9.2 Hz,2H), 4.14 (s, 2H), 1.48 (q, J=7.3 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H), 0.54(m, 4H).

Intermediate 5. (1-ethylcyclobutyl)methyl(4-nitrophenyl) Carbonate

¹H NMR (500 MHz, CDCl₃) δ 8.31 (d, J=9.4 Hz, 2H), 7.42 (d, J=9.4 Hz,2H), 4.27 (s, 2H), 1.99 - 1.83 (m, 6H), 1.63 (q, J=7.4 Hz, 2H), 0.90 (t,J=7.4 Hz, 3H).

Intermediate 6. 4-nitrophenyl((1-propylcyclobutyl)methyl) Carbonate

¹H NMR (500 MHz, CDCl₃) δ 8.31 (d, J=9.4 Hz, 2H), 7.42 (d, J=9.4 Hz,2H), 4.26 (s, 2H), 1.99 - 1.85 (m, 6H), 1.56 (m, 2H), 1.32 (m, 2H), 0.97(t, J=7.3 Hz, 3H).

TABLE 2 Ex # Structure & Name Analytical & Biology Data Method 47

LCMS, [M + H]⁺ = 462; ¹H NMR (500 MHz, DMSO-d₆) δ 8.36 (d, J=2.4 Hz,1H), 7.98 (d, J=8.5 Hz, 1H), 7.55 (m, 2H), 5.22 - 5.02 (m, 1H), 4.81-4.76 (m, 1H), 4.73 (m, 2H), 4.06 (s, 3H), 3.94 (m, 2H), 2.68 (m, 1H),2.44 (m, 1H), 2.30 -2.05 (m, 4H), 2.03 - 1.93 (m, 1H), 1.89 - 1.73 (m,3H), 1.72 -1.43 (m, 4H); hLPA₁ IC₅₀₌ 854 nM. Example 5

48

LCMS, [M + H]⁺ = 476; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (br d, J=8.5 Hz,1H), 7.63 (br s, 1H), 7.47 (br d, J=8.7 Hz, 1H), 5.19 - 5.00 (m, 1H),4.82 - 4.70 (m, 3H), 4.04 (s, 2H), 3.96 - 3.87 (m, 2H), 2.61 (m, 1H),2.44 (m, 4H), 2.28 - 2.04 (m, 4H), 2.98 (m, 1H), 1.88 - 1.71 (m, 3H),1.70 - 1.42 (m, 4H); hLPA₁ IC₅₀ = 48 nM. Example 1 49

LCMS, [M + H]⁺ = 462; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (br d, J=8.9 Hz,1H), 7.78 (br s, 1H), 7.48 (br d, J=8.5 Hz, 1H), 4.74 (m, 3H), 4.32 -4.19 (m, 2H), 4.05 (s, 3H), 2.62 (m, 1H), 2.44 (s, 3H), 2.02 - 1.92 (m,1H), 1.90 - 1.72 (m, 4H), 1.68 - 1.44 (m, 4H), 1.07 - 0.96 (m, 2H),0.80 - 0.72 (m, 2H); hLPA₁ IC₅₀ = 602 nM. Example 1 50

LCMS, [M + H]⁺ = 472; ¹H NMR (500 MHz, DMSO-d₆) δ 8.34 (d, J=2.4 Hz,1H), 7.98 (d, J=8.8 Hz, 1H), 7.52 (dd, J=8.7, 2.7 Hz, 1H), 7.33 (br s,1H), 4.77 (m, 1H), 4.72 (m, 2H), 4.06 (s, 3H), 3.79 (s, 2H), 2.72 - 2.64(m, 1H), 2.02 - 1.93 (m, 1H), 1.91 - 1.71 (m, 4H), 1.67 (m, 2H), 1.60 -1.49 (m, 2H), 1.32 - 1.17 (m, 4H), 0.79 (t, J=7.1 Hz, 3H), 0.36 (br s,2H), 0.27 (br s, 2H); hLPA₁ IC₅₀ = 28 nM. Example 5 51

LCMS, [M + H]⁺ = 258; ¹H NMR (500 MHz, DMSO-d₆) δ 8.35 (d, J=2.4 Hz,1H), 7.97 (d, J=8.9 Hz, 1H), 7.53 (dd, J=8.7, 2.6 Hz, 1H), 7.48 (br s,1H), 4.77 (m, 1H), 4.74 - 4.70 (m, 2H), 4.06 (s, 3H), 3.82 - 3.53 (m,2H), 2.69 -2.63 (m, 1H), 2.00 - 1.94 (m, 1H), 1.91 - 1.73 (m, 4H),1.71 - 1.59 (m, 2H), 1.58 - 1.46 (m, 2H), 1.30 - 1.22 (m, 2H), 0.86 -0.77 (m, 3H), 0.36 (br s, 2H), 0.28 (br s, 2H); hLPA₁ IC₅₀ = 62 nM.Example 5 52

LCMS, [M + H]⁺ = 444; ¹H NMR (500 MHz, DMSO-d₆) δ 8.37 (d, J=2.1 Hz,1H), 7.99 (d, J=8.9 Hz, 1H), 7.54 (dd, J=8.9, 2.7 Hz, 1H), 7.52 (br s,1H), 4.78 (m, 1H), 4.76 - 4.72 (m, 2H), 4.07 (s, 3H), 3.79 - 3.60 (m,2H), 2.71 -2.63 (m, 1H), 2.04 - 1.91 (m, 1H), 1.89 - 1.74 (m, 4H),1.71 - 1.63 (m, 2H), 1.59 - 1.52 (m, 2H), 1.03 (br s, 3H), 0.41 (br s,2H), 0.28 (br s, 2H); hLPA₁ IC₅₀ = 81 nM. Example 5 53

LCMS, [M + H]⁺ = 462; ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J=8.5 Hz,1H), 7.54 (br s, 1H), 7.48 (d, J=8.9 Hz, 1H), 4.82 - 4.71 (m, 3H), 4.05(s, 3H), 4.01 - 3.95 (m, 2H), 3.95 - 3.85 (m, 2H), 3.18 (br s, 3H),2.69 - 2.58 (m, 1H), 2.44 (s, 3H), 2.05 - 1.97 (m, 1H), 1.91 - 1.45 (m,9H); hLPA₁ IC₅₀ = 342 nM. Example 1 54

LCMS, [M + H]⁺ = 500; ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J=8.5 Hz,1H), 7.63 (br s, 1H), 7.48 (d, J=8.9 Hz, 1H), 4.82 - 4.67 (m, 3H), 4.04(s, 3H), 3.94 - 3.82 (m, 2H), 2.67 - 2.57 (m, 1H), 2.44 (s, 3H), 2.05 -1.97 (m, 1H), 1.92 - 1.42 (m, 14H), 1.40 - 1.28 (m, 2H), 1.23 -1.07 (m,2H), 0.87 - 0.75 (m, 3H); hLPA₁ IC₅₀ = 58 nM. Example 1 55

LCMS, [M + H]⁺ = 450; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (d, J=8.5 Hz,1H), 7.58 (br s, 1H), 7.47 (d, J=8.5 Hz, 1H), 4.81 - 4.68 (m, 3H),4.54 - 4.36 (m, 2H), 4.04 (s, 4H), 2.63 - 2.56 (m, 1H), 2.43 (s, 3H),2.01 - 1.89 (m, 2H), 1.86 - 1.74 (m, 4H), 1.64 -1.43 (m, 4H); hLPA₁ IC₅₀= 411 nM. Example 1 56

LCMS, [M + H]⁺ = 462; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (d, J=8.9 Hz,1H), 7.61 (br s, 1H), 7.47 (d, J=8.5 Hz, 1H), 4.77 (m, 1H), 4.74 (br d,J=5.5 Hz, 2H), 4.08 -3.99 (m, 5H), 3.52 - 3.33 (m, 2H), 2.66 - 2.57 (m,1H), 2.44 (s, 3H), 2.05 - 1.97 (m, 1H), 1.94 - 1.71 (m, 4H), 1.68 -1.39(m, 4H), 1.04 (t, J=7.0 Hz, 3H); hLPA₁ IC₅₀ = 885 nM. Example 1 57

LCMS, [M + H]⁺= 486; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (d, J=8.5 Hz, 1H),7.62 (br s, 1H), 7.47 (d, J=8.5 Hz, 1H), 4.80 - 4.70 (m, 3H), 4.04 (s,3H), 3.93 - 3.48 (m, 2H), 2.66 - 2.57 (m, 1H), 2.43 (s, 3H), 2.05 - 1.95(m, 1H), 1.92 - 1.33 (m, 15H), 0.77 -0.66 (m, 3H); hLPA₁ IC₅₀ = 68 nM.Example 1 58

LCMS, [M + H]⁺ = 472; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (br d, J=8.5 Hz,1H), 7.59 (br s, 1H), 7.48 (br d, J=8.5 Hz, 1H), 4.79 (m, 1H), 4.76 -4.72 (m, 2H), 4.05 (s, 3H), 3.86 - 3.50 (m, 2H), 3.30 - 3.10 (m, 1H),2.70 -2.59 (m, 1H), 2.45 (br s, 3H), 1.97 - 1.75 (m, 5H), 1.69 -1.55 (m,3H), 1.34 - 1.21 (m, 2H), 0.85 - 0.79 (m, 3H), 0.41 - 0.34 (m, 2H),0.31 - 0.26 (m, 2H); hLPA₁ IC₅₀ = 38 nM. Example 1 59

LCMS, [M + H]⁺ = 458; ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 - 7.78 (m, 1H),7.60 (br s, 1H), 7.47 (br d, J=7.6 Hz, 1H), 4.78 (m, 1H), 4.72 (br s,2H), 4.04 (s, 3H), 3.77 - 3.55 (m, 2H), 3.31 - 3.13 (m, 1H), 2.73 - 2.59(m, 1H), 2.46 (br s, 3H), 1.93 - 1.50 (m, 8H), 1.00 (m, 3H), 0.42 - 0.35(m, 2H), 0.31 - 0.23 (m, 2H); hLPA₁ IC₅₀ = 48 nM. Example 1 60

LCMS, [M+H]⁺ = 486; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (br d, J=7.7 Hz,1H), 7.61 (br s, 1H), 7.48 (br d, J=8.0 Hz, 1H), 4.79 (m, 1H), 4.73 (m,2H), 4.04 (s, 3H), 3.82 - 3.71 (m, 2H), 2.69 - 2.57 (m, 1H), 2.45 (br s,3H), 2.09 - 1.41 (m, 8H), 1.33 - 1.14 (m, 4H), 0.78 (m, 3H), 0.36 (br s,2H), 0.27 (br s, 2H); hLPA₁ IC₅₀ = 12 nM. Example 1 61

[M + H]⁺ = 481; ¹H NMR (500 MHz, CDCl₃) d 8.81 (s, 1H), 7.45 - 7.31 (m,5H), 5.54 (br. s., 1H), 5.11 (s, 2H), 4.66 (s, 2H), 4.25 (s, 3H), 2.85(tt, J=11.3, 3.5 Hz, 1H), 2.54 (s, 3H), 2.31 (d, J=14.0 Hz, 1H), 2.14 -1.96 (m, 2H), 1.93 - 1.55 (m, 5H) Acute in vivo histamine assay in CD-1mice : -63% histamine at a dose of 1 mg/kg of Example 61. Example 1 62

[M + H]⁺ = 480.2; ¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=8.6 Hz, 1H), 7.71(br d, J=8.8 Hz, 1H), 7.12 (d, J=8.1 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H),4.79 (br s, 1H), 4.69 (s, 2H), 4.22 (s, 3H), 2.92 - 2.83 (m, 1H), 2.63(s, 3H), 2.32 (s, 3H), 2.15 - 1.59 (m, 9H); hLPA₁ IC₅₀ = 148 nM. Example1 63

[M + H]⁺ = 496.2; ¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, J=8.6 Hz, 1H), 7.61(br d, J=9.2 Hz, 1H), 6.98 (d, J=9.2 Hz, 2H), 6.89 - 6.81 (m, 2H), 4.79(br s, 1H), 4.69 (s, 2H), 4.22 (s, 3H), 3.78 (s, 3H), 2.62 (s, 3H),2.12 - 2.04 (m, 2H), 2.00 - 1.58 (m, 8H); hLPA₁ IC₅₀ = 792 nM. Example 1

Example 64.(1S,3S)-3-((6-(5-((Tert-Butoxycarbonyl)amino)-1-Methyl-1H-1,2,3-Triazol-4-yl)-2-Methylpyridin-3-yl)oxy)Cyclohexane-1-CarboxylicAcid

64A. Methyl(1S,3S)-3-((6-(5-formyl-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a stirred solution of methyl(1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(synthesized analogously to the corresponding isopropyl ester Example1E; 3.28 g, 9.10 mmol) in CH₂Cl₂ (45.5 ml) were added NaHCO₃ (3.82 g,45.5 mmol) and Dess-Martin periodinane (4.63 g, 10.9 mmol) and thereaction mixture was stirred at RT for 1 h. The white solid was filteredoff through Celite® and rinsed with EtOAc. The combined filtrates werewashed with sat. aq. NaHCO₃, water, brine, dried (Na₂SO₄), andconcentrated in vacuo. The crude product was chromatographed (120 gRedisep® SiO₂ column; isocratic 60% EtOAc in Hex) to afford the titlecompound as a clear, colorless oil (3.10 g, 95%). LC-MS, [M+H]⁺ = 359.1.¹H NMR (500 MHz, CDCl₃) δ 10.96 (s, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.24(d, J=8.5 Hz, 1H), 4.77 - 4.72 (m, 1H), 4.36 (s, 3H), 3.70 (s, 3H),2.87 - 2.80 (m, 1H), 2.51 (s, 3H), 2.20 - 2.08 (m, 1H), 2.02 - 1.91 (m,3H), 1.80 - 1.59 (m, 4H).

64B.4-(((1S,3S)-3-(methoxycarbonyl)cyclohexyl)oxy)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylicAcid

To a mixture of 64A (260 mg, 0.725 mmol), NaH₂PO₄ (435 mg, 3.63 mmol),2-methyl-2-butene, (0.617 mL of a 2.0 M solution in THF; 5.80 mmol),water (0.2 mL), and t-BuOH (2 mL) at RT was added NaClO₂ (131 mg, 1.45mmol). The reaction mixture was stirred at RT for 3 h, then was pouredinto brine and extracted with EtOAc (x3). The combined organic extractswere dried (Na₂SO₄) and concentrated in vacuo to give the titlecompound. The crude acid was used in the next reaction without furtherpurification. ¹H NMR (500 MHz, CDCl₃) δ 8.52 - 8.19 (m, 1H), 7.67 - 7.40(m, 1H), 4.85 - 4.75 (m, 1H), 4.52 - 4.40 (m, 3H), 3.78 - 3.63 (m, 3H),2.90 - 2.77 (m, 1H), 2.67 - 2.53 (m, 3H), 1.99 - 1.83 (m, 3H), 1.80 -1.62 (m, 5H).

64C. Methyl(1S,3S)-3-((6-(5-((tert-butoxycarbonyl)amino)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

A mixture of 64B (60 mg, 0.160 mmol), diphenyl phosphoryl azide (63 µL,0.288 mmol), 2-methylpropan-2-ol (36 mg, 0.240 mmol), TEA (89 µL, 0.641mmol) in toluene (1 mL) was stirred at 80° C. for 1 h, then was cooledto RT and concentrated in vacuo. LC/MS indicated the formation of thedesired product. The crude product was chromatographed (12 g SiO₂;continuous gradient from 0% to 80% EtOAc in hexanes for 30 min and 80%EtOAc/hexanes for 20 min) to afford the title compound (60 mg, 0.135mmol, 84 % yield). ¹H NMR (400 MHz, CDCl₃) δ 8.00 - 7.81 (m, 1H), 7.28 -7.15 (m, 1H), 4.84 - 4.62 (m, 1H), 4.14 - 4.06 (m, 3H), 3.76 - 3.67 (m,3H), 2.92 - 2.77 (m, 1H), 2.57 - 2.49 (m, 3H), 2.25 - 2.09 (m, 1H),2.05 - 1.60 (m, 8H), 1.58 - 1.48 (m, 9H)

Example 64

To a stirred solution of 64C (30 mg, 0.067 mmol) in THF (1.5 mL), MeOH(0.100 mL) and water (0.15 mL) at RT was added 2.O M aq LiOH (0.101 mL,0.202 mmol). The mixture was stirred at 50° C. for 1 h, then was cooledto RT and acidified to pH 2.3 by dropwise addition of 1 M aq. HCl. Themixture was concentrated in vacuo and the residue was purified bypreparative HPLC ((Sunfire C18 (150 x19) mm; 5 µm; mobile phase A: 10 mMNH₄OAc in water (pH: 4.5); mobile phase B: MeCN, flow rate: 15 mL/min;time (min)/%B: 0/20, 25/60; retention time: 15.19 min)) to give thetitle compound (15 mg, 0.031 mmol, 46.5% yield). LCMS, [M + H]⁺ = 460.2.¹H NMR (400 MHz, CDCl₃) δ 8.03 - 7.85 (m, 1H), 7.26 - 7.22 (m, 1H),4.77 - 4.66 (m, 1H), 4.15 - 4.05 (m, 3H), 2.92 - 2.75 (m, 1H), 2.56 -2.43 (m, 3H), 2.23 - 2.08 (m, 1H), 2.05 - 1.85 (m, 3H), 1.82 - 1.61 (m,4H), 1.60 - 1.48 (m, 9H). LCMS, [M + H]⁺ = 446.2. hLPA₁ IC₅₀ = 54 nM.

Table 3 below lists additional Examples. Some of these Examples (103 to107) were synthesized by using the triazole-ethanol intermediate 7(shown below). Specifically, the intermediate alcohol 7 was converted tothe following examples by using the same method and procedure as shownin Scheme 1 and exemplified by the 5-step conversion of intermediate 1Eto Example 1.

Intermediate 7. Methyl(1S,3S)-3-((6-(5-(2-hydroxyethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

7A. Methyl(1S,3S)-3-((2-methyl-6-(1-methyl-5-vinyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a 0° C. suspension of Ph₃PCH₃Br (3.77 g, 10.6 mmol) in THF (70 mL)was added KOtBu (0.947 g, 8.44 mmol), and the reaction mixture wasstirred at 0° C. for 30 min. A solution of Example 241A (2.52 g, 7.03mmol) in THF (10 mL) was added to the reaction, which was stirred at 0°C. for 30 min, then was allowed to warm to RT. The reaction was stirredfor 1 h at RT, then was quenched with satd aq. NH₄Cl and diluted withEtOAc. The aqueous layer was extracted with EtOAc (2 X 25 mL). Thecombined organic extracts were washed with brine, dried (Na₂SO₄), andconcentrated in vacuo. The crude product was chromatographed (220 gRedisep® SiO₂ column; continuous gradient from 0-60% EtOAc in hexane) togive the title compound as a white gum (2.2 g, 88%). LC-MS, [M+H]⁺ =357.0. ¹H NMR (500 MHz, CDCl₃) δ 7.91 (d, J=8.5 Hz, 1H), 7.42 (dd,J=18.3, 12.0 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 5.93 - 5.88 (m, 1H),5.70 - 5.66 (m, 1H), 4.71 (br s, 1H), 4.15 (s, 3H), 3.70 (s, 3H), 2.84(tt, J=10.5, 3.9 Hz, 1H), 2.53 (s, 3H), 2.16 (br d, J=13.8 Hz, 1H),2.02 - 1.87 (m, 3H), 1.87 - 1.71 (m, 1H), 1.71 - 1.54 (m, 3H).

Intermediate 7

To a 0° C. solution of Intermediate 7A (1.45 g, 4.07 mmol) in THF (13.6ml) was added dropwise 9-BBN (17.9 mL of a 0.5 M solution in THF; 8.95mmol). The ice bath was removed and the reaction was heated at 65° C.for 4 h, then was cooled to 0° C. A solution of sodium perboratetetrahydrate (2.50 g, 16.3 mmol) in water (10 mL) was added. Thereaction was warmed to RT and stirred at RT for 18 h; water was thenadded. The aqueous layer was extracted with EtOAc (2 x 20 mL). Thecombined organic extracts were washed with brine, dried (MgSO₄) andconcentrated in vacuo. The crude product was chromatographed (120 gRedisep® SiO₂ column; continuous gradient from 0-100% EtOAc in Hex) toafford the title compound as a colorless oil (0.37 g, 24 %). LC-MS,[M+H]⁺ = 375.1. ¹H NMR (400 MHz, CDCl₃) δ 7.92 (d, J=8.6 Hz, 1H), 7.30 -7.25 (m, 1H), 6.71 - 6.42 (m, 1H), 4.74 - 4.68 (m, 1H), 4.06 - 3.98 (m,5H), 3.70 (s, 3H), 3.26 (td, J=5.6, 1.4 Hz, 2H), 2.83 (tt, J=10.3, 3.9Hz, 1H), 2.51 (s, 3H), 2.14 (dt, J=13.9, 4.3 Hz, 1H), 2.02 - 1.87 (m,3H), 1.82 - 1.56 (m, 4H).

TABLE 3 Ex # Structure & Name Analytical & Biology Data Method 65

LCMS, [M + H]⁺ = 460.2; ¹H NMR (500 MHz, CDCl₃) δ 8.24 - 8.09 (m, 1H),7.97 - 7.82 (m, 1H), 4.93 - 4.80 (m, 1H), 4.59 -4.38 (m, 7H), 4.29 -4.14 (m, 3H), 4.12 - 3.95 (m, 3H), 3.00 - 2.85 (m, 1H), 2.84 - 2.63 (m,3H), 2.28 -2.13 (m, 1H), 2.01 - 1.51 (m, 9H), 1.11 - 0.75 (m, 9H); hLPA₁IC₅₀ = 75 nM. Example 64 & Scheme 7 66

LCMS, [M + H]⁺ = 444.0; ¹H NMR (500 MHz, DMSO-d₆) δ 7.68 - 7.42 (m, 2H),5.14 - 4.94 (m, 1H), 4.86 - 4.67 (m, 3H), 3.69 - 3.29 (m, 3H), 3.24-3.11 (m, 1H), 2.37 - 1.28 (m, 16H); hLPA₁ IC₅₀ = 68 nM. Example 64 &Scheme 7 67

LCMS, [M + H]⁺ = 446.2; ¹H NMR (400 MHz, CDCl₃) δ 8.23 - 8.06 (m, 1H),8.02 - 7.88 (m, 1H), 4.96 - 4.78 (m, 1H), 4.13 -4.03 (m, 3H), 3.93 -3.79 (m, 2H), 2.98 - 2.86 (m, 1H), 2.83 - 2.68 (m, 3H), 2.28 - 2.11 (m,1H), 2.02 -1.62 (m, 7H), 1.10 - 0.90 (m, 9H); hLPA₁ IC₅₀ = 72 nM.Example 64 & Scheme 7 68

LCMS, [M + H]⁺ = 418.2; ¹H NMR (400 MHz, CDCl₃) δ 8.23 - 8.08 (m, 1H),8.00 - 7.85 (m, 1H), 5.48 - 5.04 (m, 1H), 4.89 -4.79 (m, 1H), 4.21 -4.00 (m, 5H), 2.99 - 2.86 (m, 1H), 2.82 - 2.70 (m, 3H), 2.27 - 2.14 (m,1H), 2.02 -1.59 (m, 9H), 1.04 - 0.92 (m, 3H); hLPA₁ IC₅₀ = 89 nM.Example 64 & Scheme 7 69

LCMS, [M + H]⁺ = 444.0; ¹H NMR (500 MHz, DMSO-d₆) δ 7.54 - 7.37 (m, 1H),7.32 - 7.13 (m, 1H), 4.62 - 4.44 (m, 1H), 4.05 - 3.93 (m, 1H), 3.64 (s,3H), 2.28 - 2.11 (m, 6H), 1.85 - 1.54 (m, 4H), 1.49 - 1.17 (m, 4H), 1.06-0.87 (m, 4H), 0.26 to -0.04 (m, 4H); hLPA₁ IC₅₀ = 85 nM. Example 64 &Scheme 7 70

LCMS, [M + H]⁺ = 418.2; ¹H NMR (400 MHz, CDCl₃) δ 8.27 - 8.09 (m, 1H),8.01 - 7.88 (m, 1H), 6.66 - 6.12 (m, 1H), 5.05 -4.79 (m, 2H), 4.15 -3.98 (m, 3H), 2.99 - 2.86 (m, 1H), 2.82 - 2.70 (m, 3H), 2.29 - 2.15 (m,1H), 2.06 -1.60 (m, 8H), 1.38 - 1.16 (m, 6H); hLPA₁ IC₅₀ = 129 nM.Example 64 & Scheme 7 71

LCMS, [M + H]⁺ = 446.1; ¹H NMR (400 MHz, CDCl₃) δ 8.20 - 8.01 (m, 1H),7.80 - 7.65 (m, 1H), 4.93 - 4.73 (m, 1H), 4.25 -4.14 (m, 2H), 4.11 -3.97 (m, 3H), 2.73 - 2.64 (m, 4H), 2.25 - 1.61 (m, 11H), 1.45 - 1.26 (m,4H), 1.00 -0.84 (m, 3H); hLPA₁ IC₅₀ = 6 nM. Example 64 & Scheme 7 72

LCMS, [M + H]⁺ = 480.1; ¹H NMR (400 MHz, CDCl₃) δ 8.13 - 8.02 (m, 1H),7.83 - 7.72 (m, 1H), 7.45 - 7.31 (m, 5H), 5.92 -5.75 (m, 1H), 4.87 -4.76 (m, 1H), 4.06 - 3.92 (m, 3H), 2.97 - 2.87 (m, 2H), 2.76 - 2.72 (m,1H), 2.70 -2.61 (m, 3H), 2.21 - 2.11 (m, 1H), 2.05 - 1.73 (m, 6H),1.70 - 1.56 (m, 4H); hLPA₁ IC₅₀ = 26 nM. Example 64 & Scheme 7 73

LCMS, [M + H]⁺ = 444.1; ¹H NMR (400 MHz, CD₃CN) δ 7.97 - 7.69 (m, 2H),4.95 - 4.76 (m, 1H), 4.29 - 4.01 (m, 2H), 3.92 -3.75 (m, 3H), 2.83 -2.49 (m, 4H), 2.10 - 1.91 (m, 2H), 1.83 - 1.33 (m, 8H), 0.84 - 0.56 (m,1H), 0.45 -0.17 (m, 2H), 0.06 -0.08 (m, 2H); hLPA₁ IC₅₀ = 11 nM. Example64 & Scheme 7 74

LCMS, [M + H]⁺ = 430.2; ¹H NMR (400 MHz, CD₃CN) δ 8.08 - 7.85 (m, 2H),5.08 - 4.76 (m, 1H), 4.14 - 3.84 (m, 5H), 2.87 -2.75 (m, 1H), 2.74 -2.68 (m, 3H), 2.67 - 2.63 (m, 1H), 2.19 - 2.07 (m, 1H), 1.93 - 1.86 (m,3H), 1.84 -1.56 (m, 4H), 1.29 - 1.03 (m, 1H), 0.71 - 0.52 (m, 2H),0.45 - 0.13 (m, 2H); hLPA₁ IC₅₀ = 14 nM. Example 64 & Scheme 7 75

LCMS, [M + H]⁺ = 444.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.81 - 7.65 (m, 1H),7.55 - 7.39 (m, 1H), 4.80 - 4.68 (m, 2H), 4.01 (br d, J=4.7 Hz, 3H),3.88 (s, 4H), 2.71 - 2.61 (m, 1H), 2.58 - 2.54 (m, 5H), 2.45 - 2.29 (m,4H), 2.10 - 1.40 (m, 7H); hLPA₁ IC₅₀ = 22 nM. Example 64 & Scheme 7 76

LCMS, [M + H]⁺ = 472.2; ¹H NMR (500 MHz, CDCl₃) δ 8.21 - 8.10 (m, 1H),7.95 - 7.85 (m, 1H), 7.18 - 6.61 (m, 1H), 4.91 -4.76 (m, 1H), 4.13 -4.04 (m, 3H), 4.01 - 3.91 (m, 2H), 3.00 - 2.84 (m, 1H), 2.81 - 2.70 (m,3H), 2.29 -2.14 (m, 1H), 2.04 - 1.40 (m, 14H), 1.40 - 1.08 (m, 3H),1.05 - 0.86 (m, 2H); hLPA₁ IC₅₀ = 19 nM. Example 64 & Scheme 7 77

LCMS, [M + H]⁺ = 446.1; ¹H NMR (400 MHz, CDCl₃) δ 8.07 - 7.94 (m, 1H),7.61 - 7.43 (m, 1H), 4.88 - 4.70 (m, 1H), 4.29 -4.17 (m, 2H), 4.13 -4.03 (m, 3H), 2.99 - 2.87 (m, 1H), 2.66 - 2.59 (m, 3H), 2.18 - 2.06 (m,4H), 1.80 -1.68 (m, 6H), 1.63 - 1.55 (m, 2H), 1.02 - 0.91 (m, 6H); hLPA₁IC₅₀ = 20 nM. Example 64 & Scheme 7 78

LCMS, [M + H]⁺ = 432.1; ¹H NMR (500 MHz, CDCl₃) δ 8.18 - 8.06 (m, 1H),7.81 - 7.69 (m, 1H), 4.94 - 4.74 (m, 1H), 4.18 -4.02 (m, 3H), 3.99 -3.88 (m, 2H), 2.98 - 2.85 (m, 1H), 2.78 - 2.64 (m, 3H), 2.23 - 1.62 (m,10H), 0.98 (d, J=6.6 Hz, 6H); hLPA₁ IC₅₀ = 29 nM. Example 64 & Scheme 779

LCMS, [M + H]⁺ = 458.2; ¹H NMR (400 MHz, CDCl₃) δ 8.68 - 8.29 (m, 2H),8.17 (d, J=8.8 Hz, 1H), 7.97 - 7.88 (m, 1H), 4.92 - 4.77 (m, 1H), 4.13-4.01 (m, 5H), 2.97 - 2.86 (m, 1H), 2.80 - 2.75 (m, 3H), 2.33 - 2.15 (m,2H), 2.00 - 1.53 (m, 13H), 1.35 - 1.19 (m, 2H); hLPA₁ IC₅₀= 32 nM.Example 64 & Scheme 7 80

LCMS, [M + H]⁺ = 466.0; ¹H NMR (500 MHz, DMSO-d₆) δ 7.49 - 7.14 (m, 7H),5.27 - 4.98 (m, 2H), 4.83 - 4.66 (m, 1H), 4.01 - 3.76 (m, 3H), 2.60-2.54 (m, 4H), 2.37 - 2.20 (m, 3H), 2.13 - 1.99 (m, 1H), 1.95 - 1.73 (m,2H), 1.70 - 1.41 (m, 4H). hLPA₁ IC₅₀ = 37 nM. Example 64 & Scheme 7 81

LCMS, [M + H]⁺ = 430.4; ¹H NMR (500 MHz, DMSO-d₆) δ 8.29 (br d, J=2.4Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.52 (dd, J=8.9, 2.7 Hz, 1H), 4.77 (brs, 1H), 4.01 (br s, 1H), 3.87 (s, 3H), 2.65 (br s, 1H), 2.57 - 2.55 (m,2H), 2.24 - 1.31 (m, 14H); hLPA₁ IC₅₀ = 56 nM. Example 64 & Scheme 7 82

LCMS, [M + H]⁺ = 430.3; ¹H NMR (500 MHz, DMSO-d₆) δ 9.84 - 9.04 (m, 1H),8.29 (d, J=2.4 Hz, 1H), 7.87 (d, J=8.9 Hz, 1H), 7.52 (dd, J=8.7, 2.6 Hz,1H), 4.76 (br s, 1H), 4.19 (br s, 1H), 3.88 (s, 3H), 3.61 - 3.47 (m,1H), 2.01 - 1.42 (m, 9H), 1.39 -0.82 (m, 3H), 0.61 - 0.16 (m, 4H); hLPA₁IC₅₀ = 79 nM. Example 64 & Scheme 7 83

LCMS, [M + H]⁺ = 416.2; ¹H NMR (500 MHz, DMSO-d₆) δ 8.08 (br s, 1H),7.67 (br d, J=8.9 Hz, 1H), 7.31 (dd, J=8.7, 2.3 Hz, 1H), 4.55 (br s,1H), 3.66 (s, 3H), 2.44 (br s, 1H), 2.34 (s, 2H), 1.73 (br d, J=13.4 Hz,1H), 1.66 -1.54 (m, 3H), 1.44 (br d, J=8.5 Hz, 2H), 1.37 - 1.25 (m, 2H),1.01 - 0.63 (m, 1H), 0.42 - -0.20 (m, 4H); hLPA₁ IC₅₀ = 178 nM. Example64 & Scheme 7 84

LCMS, [M + H]⁺ = 430.1; ¹H NMR (500 MHz, DMSO-d₆) δ 8.26 (d, J=2.4 Hz,1H), 7.85 (d, J=8.9 Hz, 1H), 7.50 (dd, J=8.5, 2.4 Hz, 1H), 4.83 - 4.67(m, 1H), 4.15 - 3.99 (m, 1H), 3.85 (s, 3H), 2.67 - 2.56 (m, 1H), 2.55 -2.53 (m, 2H), 1.95 - 1.80 (m, 2H), 1.79 - 1.23 (m, 8H), 0.48 -0.20 (m,4H); hLPA₁ IC₅₀ = 38 nM. Example 64 & Scheme 7 85

LCMS, [M + H]⁺ = 432.3; ¹H NMR (500 MHz, DMSO-d₆) δ 8.26 (br s, 1H),7.87 (br d, J=8.9 Hz, 1H), 7.50 (br d, J=6.7 Hz, 1H), 4.73 (br s, 1H),4.19 -3.42 (m, 3H), 2.64 (br s, 1H), 2.55 (s, 1H), 1.89 (br d, J=18.0Hz, 1H), 1.75 (br s, 1H), 1.69 - 1.50 (m, 6H), 1.45 - 1.34 (m, 2H), 1.27(br s, 3H), 0.82 (br d, J=6.7 Hz, 6H); hLPA₁ IC₅₀ = 115 nM. Example 64 &Scheme 7 86

LCMS, [M + H]⁺ = 458.2; ¹H NMR (500 MHz, DMSO-d₆) δ 8.24 (d, J=2.4 Hz,1H), 7.86 (d, J=8.5 Hz, 1H), 7.50 (dd, J=8.7, 2.6 Hz, 1H), 4.73 (br s,1H), 4.01 - 3.59 (m, 3H), 2.60 (br s, 1H), 2.56 - 2.55 (m, 3H), 2.06 -0.57 (m, 18H); hLPA₁ IC₅₀ = 36 nM. Example 64 & Scheme 7 87

LCMS, [M + H]⁺ = 418.2; ¹H NMR (500 MHz, DMSO-d₆) δ 8.25 (d, J=2.4 Hz,1H), 7.87 (d, J=8.9 Hz, 1H), 7.51 (dd, J=8.7, 2.6 Hz, 1H), 4.74 (br s,1H), 3.86 (s, 3H), 2.58 (br d, J=4.6 Hz, 1H), 2.56 - 2.55 (m, 3H),1.95 - 1.43 (m, 9H), 1.04 - 0.51 (m, 6H); hLPA₁ IC₅₀ = 219 nM. Example64 & Scheme 7 88

LCMS, [M + H]⁺ = 432.2; ¹H NMR (500 MHz, DMSO-d₆) δ 8.28 (d, J=2.4 Hz,1H), 7.88 (d, J=8.5 Hz, 1H), 7.52 (dd, J=8.7, 2.6 Hz, 1H), 4.75 (br s,1H), 4.01 (br s, 1H), 3.87 (s, 3H), 2.61 (br d, J=3.7 Hz, 1H), 2.56 -2.55 (m, 2H), 1.97 - 1.83 (m, 2H), 1.75 (br s, 2H), 1.70 - 1.47 (m, 6H),1.25 (br d, J=8.2 Hz, 3H), 0.82 (br s, 3H); hLPA₁ IC₅₀ = 34 nM. Example64 & Scheme 7 89

LCMS, [M + H]⁺ = 418.2; ¹H NMR (500 MHz, DMSO-d₆) δ 8.51 - 8.09 (m, 1H),7.98 - 7.25 (m, 2H), 4.75 (br s, 1H), 4.14 -3.91 (m, 2H), 3.89 - 3.79(m, 3H), 2.69 - 2.59 (m, 3H), 1.88 (br s, 2H), 1.73 (br s, 3H), 1.68 -1.51 (m, 6H), 0.84 (br s, 3H); hLPA₁ IC₅₀ = 66 nM. Example 64 & Scheme 790

LCMS, [M + H]⁺ = 430.1; ¹H NMR (500 MHz, DMSO-d₆) δ 9.45 - 9.28 (m, 1H),8.52 - 8.10 (m, 1H), 7.88 (br d, J=8.9 Hz, 1H), 7.52 (dd, J=8.9, 2.4 Hz,1H), 5.07 - 4.90 (m, 1H), 4.77 (br s, 1H), 3.87 (s, 3H), 2.73 - 2.62 (m,1H), 2.58 - 2.56 (m, 2H), 2.03 - 1.92 (m, 1H), 1.89 -1.39 (m, 13H);hLPA₁ IC₅₀ = 149 nM. Example 64 & Scheme 7 91

LCMS, [M + H]⁺ = 465.9; ¹H NMR (500 MHz, DMSO-d₆) δ 8.19 (br s, 1H),7.86 (d, J=8.9 Hz, 1H), 7.49 (br dd, J=8.7, 2.6 Hz, 1H), 7.43 - 7.28 (m,4H), 5.99 - 5.62 (m, 1H), 4.75 (br s, 1H), 3.91 (s, 1H), 3.86 (s, 2H),2.67 (br s, 1H), 2.58 - 2.55 (m, 3H), 2.00 - 1.92 (m, 1H), 1.89 -1.74(m, 3H), 1.72 - 1.46 (m, 6H); hLPA₁ IC₅₀ = 35 nM. Example 64 & Scheme 792

LCMS, [M + H]⁺ = 534.0; ¹H NMR (DMSO-d₆) δ: 8.25 (br d, J=8.5 Hz, 1H),7.93 (br d, J=8.5 Hz, 1H), 7.53 (br s, 1H), 7.16-7.43 (m, 5H), 5.01 (m,3H), 4.80 (br d, J=4.6 Hz, 2H), 4.06 (br s, 3H), 2.55 (m, 1H), 1.20-2.15(m, 8H); hLPA₁ IC₅₀ = 14 nM. Example 1 93

LCMS, [M + H]⁺ = 500.0; ¹H NMR (DMSO-d₆) δ: 8.25 (br d, J=8.9 Hz, 1H),7.94 (br d, J=8.9 Hz, 1H), 7.35 (br s, 1H), 5.00 (br s, 2H), 4.75 (br s,2H), 4.06 (s, 3H), 3.09-3.82 (m, 1H), 2.56-2.62 (m, 1H), 1.35-2.14 (m,9H), 0.82 (br d, J=4.9 Hz, 6H); hLPA₁ IC₅₀ = 25 nM. Example 1 94

LCMS, [M + H]⁺ = 499.8; ¹H NMR (DMSO-d₆) δ: 8.25 (d, J=8.9 Hz, 1H), 7.94(br d, J=8.9 Hz, 1H), 7.32 (br s, 1H), 5.00 (br s, 2H), 4.75 (br s, 2H),4.06 (s, 3H), 3.92 (br s, 1H), 2.56-2.62 (m, 1H), 1.18-2.15 (m, 12H),0.84 (br s, 3H); hLPA₁ IC₅₀ = 14 nM. Example 1 95

LCMS, [M + H]⁺ = 486.1; ¹H NMR (DMSO-d₆) δ: 8.25 (d, J=8.9 Hz, 1H), 7.94(br d, J=8.9 Hz, 1H), 7.34 (br s, 1H), 5.01 (br s, 1H), 4.76 (br s, 2H),4.07 (s, 3H), 3.88 (br s, 2H), 2.58 (br s, 1H), 1.14-2.17 (m, 10H), 0.83(br s, 3H); hLPA₁ IC₅₀ = 867 nM. Example 1 96

LCMS, [M + H]⁺ = 512.0; ¹H NMR (DMSO-d₆) δ: 8.25 (br d, J=8.9 Hz, 1H),7.94 (br d, J=9.2 Hz, 1H), 7.27 (br t, J=5.3 Hz, 1H), 4.96-5.10 (m, 1H),4.83-4.96 (m, 1H), 4.57-4.80 (m, 2H), 4.06 (s, 3H), 2.56-2.63 (m, 1H),0.95-2.17 (m, 16H); hLPA₁ IC₅₀ = 33 nM. Example 1 97

LCMS, [M + H]⁺ = 518.2; ¹H NMR (METHANOL-d₄) δ: 8.27 (d, J=8.8 Hz, 1H),7.86 (d, J=9.0 Hz, 1H), 4.68-5.05 (m, 1H), 4.29-4.52 (m, 4H), 4.19 (s,3H), 4.06 (br t, J=5.8 Hz, 2H), 2.73 (br t, J=10.2 Hz, 1H), 1.38-2.30(m, 12H); hLPA₁ IC₅₀ = 25 nM. Example 1 98

LCMS, [M + H]⁺ = 516.2; ¹H NMR (DMSO-d₆) δ: 8.16 (br d, J=8.5 Hz, 1H),7.82 (br d, J=8.5 Hz, 1H), 7.54 (br s, 1H), 6.97-7.43 (m, 6H), 5.02 (s,2H), 4.93 (br s, 1H), 4.77 (br d, J=4.9 Hz, 2H), 4.09 (s, 3H), 2.66 (brt, J=10.8 Hz, 1H), 1.32-2.17 (m, 8H); hLPA₁ IC₅₀ = 33 nM. Example 1 99

LCMS, [M + H]⁺ = 482.1; ¹H NMR (DMSO-d₆) δ: 7.88 (br d, J=8.4 Hz, 1H),7.64 (br d, J=8.2 Hz, 1H), 6.99-7.44 (m, 1H), 4.65 (br dd, J=11.7, 4.8Hz, 4H), 3.36-3.81 (m, 5H), 2.63-2.80 (m, 1H), 0.98-2.24 (m, 15H); hLPA₁IC₅₀ = 71 nM. Example 1 100

LCMS, [M + H]⁺ = 482.3; ¹H NMR (DMSO-d₆) δ: 8.16 (br d, J=8.9 Hz, 1H),7.83 (d, J=8.9 Hz, 1H), 7.35 (br s, 1H), 7.01-7.28 (m, 1H), 4.94 (br s,1H), 4.72 (br d, J=4.3 Hz, 2H), 4.10 (s, 3H), 3.94 (br s, 2H), 2.67 (brt, J=10.7 Hz, 1H), 1.17-2.18 (m, 12H), 0.86 (br t, J=6.7 Hz, 3H); hLPA₁IC₅₀ = 39 nM. Example 1 101

LCMS, [M + H]⁺ = 468.2; ¹H NMR (DMSO-d₆) δ: 8.16 (br d, J=8.8 Hz, 1H),7.83 (d, J=8.9 Hz, 1H), 7.36 (br s, 1H), 6.97-7.30 (m, 1H), 4.94 (br s,1H), 4.72 (br d, J=4.6 Hz, 2H), 4.10 (s, 3H), 3.90 (br d, J=8.2 Hz, 2H),2.67 (br t, J=10.8 Hz, 1H), 1.33-2.15 (m, 10H), 0.84 (br t, J=6.9 Hz,3H); hLPA₁ IC₅₀ = 2025 nM. Example 1 102

LCMS, [M + H]⁺ = 510.3; ¹H NMR (DMSO-d₆) δ: 7.95 (br d, J=8.5 Hz, 1H),7.85 (br s, 1H), 7.60 (br d, J=8.5 Hz, 1H), 7.27-7.42 (m, 5H), 5.02 (s,2H), 4.83 (br s, 1H), 4.49-4.73 (m, 7H), 4.12 (s, 3H), 2.65 (br t,J=10.5 Hz, 1H), 1.33-2.16 (m, 8H); hLPA₁ IC₅₀ = 30 nM. Example 1 103

LCMS, [M + H]⁺ = 528.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (br d, J=8.2Hz, 1H), 7.74 - 7.65 (m, 1H), 7.55 - 7.44 (m, 2H), 7.37 (br d, J=7.3 Hz,3H), 5.06 (s, 2H), 4.77 (br s, 1H), 3.98 (s, 3H), 3.53 -3.15 (m, 3H),2.64 (br d, J=3.7 Hz, 1H), 2.56 (s, 1H), 2.45 (s, 3H), 2.09 -1.42 (m,8H); hLPA₁ IC₅₀ = 595 nM. Example 1 & Scheme 1 via Intermediate 7 104

LCMS, [M + H]⁺ = 474.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J=8.5 Hz,1H), 7.48 (br d, J=8.2 Hz, 2H), 4.78 (br s, 1H), 4.00 (s, 3H), 3.61 (s,3H), 3.39 - 3.22 (m, 6H), 2.74 -2.56 (m, 1H), 2.02 (br s, 1H), 1.94 -1.40 (m, 7H), 0.84 (s, 9H); hLPA₁ IC₅₀ = 1364 nM. Example 1 & Scheme 1via Intermediate 7 105

LCMS, [M + H]⁺ = 472.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.81 (br d, J=8.5Hz, 1H), 7.47 (d, J=8.9 Hz, 1H), 7.38 (br s, 1H), 4.97 - 4.68 (m, 2H),3.99 (s, 3H), 3.42 - 3.13 (m, 2H), 2.64 (br s, 1H), 2.56 (s, 3H), 2.45(s, 3H), 2.10 - 1.39 (m, 15H); hLPA₁ IC₅₀ = 1833 nM. Example 1 & Scheme1 via Intermediate 7 106

LCMS, [M + H]⁺ = 493.9; ¹H NMR (500 MHz, DMSO-d₆) δ 7.93 - 7.74 (m, 1H),7.63 (br s, 1H), 7.57 - 7.41 (m, 1H), 7.40 -7.20 (m, 4H), 4.98 (s, 2H),4.82 - 4.60 (m, 1H), 4.08 -3.78 (m, 3H), 3.51 - 3.20 (m, 2H), 3.00 (s,1H), 2.56 (s, 3H), 2.43 - 2.36 (m, 2H), 1.77 - 1.43 (m, 5H), 1.33 - 1.10(m, 2H), 0.78 (br d, J=6.1 Hz, 2H); hLPA₁ IC₅₀ = 525 nM. Example 1 &Scheme 1 via Intermediate 7 107

LCMS, [M + H]⁺ = 460.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.81 (br d, J=8.5Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.43 (br s, 1H), 4.77 (br s, 1H), 3.99(s, 3H), 3.88 (br t, J=6.4 Hz, 1H), 3.42 - 3.21 (m, 3H), 2.64 (br t,J=10.4 Hz, 1H), 2.55 (s, 2H), 2.45 (s, 3H), 2.10 - 1.96 (m, 1H), 1.90 -1.74 (m, 3H), 1.69 -1.40 (m, 6H), 1.33 - 1.20 (m, 2H), 0.86 (br t, J=7.2Hz, 3H); hLPA₁ IC₅₀ = 1464 nM. Example 1 & Scheme 1 via Intermediate 7

Example 108.(1S,3S)-3-((6-(5-((3-(Cyclobutylmethyl)-3-Methylureido)Methyl)-1-Methyl-1H-1,2,3-Triazol-4-yl)-2-Methylpyridin-3-yl)oxy)Cyclohexanecarboxylic Acid

108A. (Cyclobutylmethyl)(Methyl)Carbamic Chloride

To a 0° C. solution of triphosgene (269 mg, 0.91 mmol) in CH₂Cl₂ (5 mL)was added dropwise a solution of 1-cyclobutyl-N-methylmethanamine (150mg, 1.51 mmol) and pyridine (183 µL, 2.27 mmol) in CH₂Cl₂ (3 mL). Thereaction mixture was allowed to warm to RT over 30 min, then wasquenched by cautious addition of 0.1 N aq. HCl (5 mL). The aqueous phasewas extracted with CH₂Cl₂ (2 X 5 mL). The combined organic extracts weredried (MgSO₄) and concentrated in vacuo to give the title compound (239mg, 1.48 mmol, 98% yield) as a yellow oil, which was used in the nextstep without further purification. ¹H NMR (500 MHz, CDCl₃) δ 3.57 - 3.44(m, 2H), 3.14 - 3.00 (m, 3H), 2.66 (dt, J=15.7, 7.8 Hz, 1H), 2.17 - 2.04(m, 2H), 2.02 - 1.73 (m, 4H)

108B. (1S,3S)-isopropyl3-((6-(5-((3-(cyclobutylmethyl)-3-methylureido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate

108A (18 mg, 0.11 mmol) was added to a solution of Example 1H (28 mg,0.072 mmol) and TEA (12 µL, 0.087 mmol) in CH₂Cl₂ (1 mL) at 0 ⁰C,followed by DMAP (1 mg, 7 µmol). After 10 min at 0 ⁰C, the reactionmixture was allowed to warm to RT and stirred at RT for 2 h, then wasconcentrated in vacuo. The crude product was chromatographed (4 g SiO₂;continuous gradient from 0% to 100% EtOAc/Hexane over 10 min) to givethe title compound (35 mg, 0.068 mmol, 94% yield) as a clear oil. ¹H NMR(500 MHz, CDCl₃) δ 8.07 (d, J=8.5 Hz, 1H), 7.32 - 7.27 (m, 1H), 6.92 (brt, J=6.1 Hz, 1H), 5.05 (quin, J=6.3 Hz, 1H), 4.75 - 4.69 (m, 1H), 4.60(d, J=6.3 Hz, 2H), 4.28 (s, 3H), 3.24 (d, J=7.2 Hz, 2H), 2.87 - 2.74 (m,4H), 2.55 (s, 3H), 2.48 (dt, J=15.5, 7.9 Hz, 1H), 2.14 - 2.07 (m, 1H),2.03 - 1.58 (m, 13H), 1.29 - 1.24 (m, 6H)

Example 108

A mixture of 108B (32 mg, 0.062 mmol) and aq. 1.0 M NaOH (0.31 mL, 0.31mmol) in THF (1 mL) was stirred at 45° C. for 18 h, then was cooled toRT and acidified to pH = 4 with TFA and concentrated in vacuo. The crudeproduct was purified by preparative HPLC (Sunfire C18 30 x 100 mmcolumn; detection at 220 nm; flow rate = 40 mL/min; continuous gradientfrom 30% B to 100% B over 10 min + 2 min hold time at 100% B, where A =90:10:0.1 H₂O:MeCN:TFA and B = 90:10:0.1 MeCN:H₂O:TFA) to give the titlecompound (TFA salt; 35 mg, 0.059 mmol, 94% yield) as a clear oil. ¹H NMR(500 MHz, CDCl₃) δ 8.21 (d, J=8.8 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 4.91(br. s., 1H), 4.55 (s, 2H), 4.21 (s, 3H), 3.34 (d, J=7.2 Hz, 2H), 3.00 -2.85 (m, 4H), 2.80 (s, 3H), 2.56 (dt, J=15.002, 7.7 Hz, 1H), 2.26 - 2.12(m, 1H), 2.09 - 1.62 (m, 14H); [M + H]⁺ = 471.1; hLPA₁ IC₅₀ = 82 nM.

The examples in Table 4 below were synthesized according to theprocedures described for the preparation of Example 108.

TABLE 4 Ex # Structure & Name Analytical & Biological Data 109

LCMS, [M+H]⁺ = 493.1; ¹H NMR (500 MHz, CDCl₃) ö 8.21 (d, J=9.1 Hz, 1H),8.00 (d, J=9.1 Hz, 1H), 7.44 - 7.11 (m, 5H), 4.89 (br. s., 1H), 4.68-4.47 (m, 4H), 4.15 (br. s., 3H), 2.98 (s, 3H), 2.88 (br. s., 1H), 2.73(s, 3H), 2.26 - 2.12 (m, 1H), 2.03 - 1.58 (m, 7H); hLPA₁ IC₅₀ = 85 nM.110

LCMS, [M+H]⁺ = 445.5; ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d, J=9.1 Hz, 1H),8.00 (d, J=9.1 Hz, 1H), 4.90 (br. s., 1H), 4.56 (s, 2H), 4.22 (s, 3H),3.26 (t, J=7.3 Hz, 2H), 2.99 - 2.86 (m, 4H), 2.79 (s, 3H), 2.27 -2.15(m, 1H), 2.08 - 1.76 (m, 6H), 1.75 - 1.51 (m, 3H), 0.90 (t, J=7.4 Hz,3H); hLPA₁ IC₅₀ = 217 nM. 111

LCMS, [M+H]⁺ = 473.4; ¹H NMR (500 MHz, DMSO-d₆) δ 7.93 (br d, J=7.0 Hz,1H), 7.63 (br d, J=8.5 Hz, 1H), 4.82 (br s, 1H), 4.54 (s, 2H), 4.11 (s,3H), 3.64 (br s, 1H), 3.10 (br t, J=7.3 Hz, 2H), 2.73 (s, 3H), 2.62 (brt, J=10.7 Hz, 1H), 2.08 -1.97 (m, 1H), 1.92 - 1.72 (m, 3H), 1.70 - 1.44(m, 5H), 1.34 -1.23 (m, 2H), 1.20 - 0.98 (m, 5H), 0.74 (t, J=7.3 Hz,3H); hLPA₁ IC₅₀ = 226 nM

Example 112.(1S,3S)-3-((6-(5-((3-benzylureido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylicacid, TFA salt

112A. Methyl(1S,3S)-3-((6-(5-((3-benzylureido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of methyl(1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(synthesized analogously to the corresponding isopropyl ester Example1H, 30 mg, 0.083 mmol) in DCE (1.7 mL) was added Et₃N (29 µL, 0.21 mmol)followed by CDI (27.1 mg, 0.17 mmol). The reaction was stirred at RT for1 h, after which benzylamine (23 µL, 0.21 mmol) was added. The reactionwas stirred at RT for 30 min and then was heated at 80° C. for 30 min,then was cooled to RT. Water was added to the reaction mixture, whichwas neutralized to pH 7 with 1 M aq. HCl, then was extracted with EtOAc(3x). The combined organic extracts were washed with brine, dried(Na₂SO₄) and concentrated in vacuo to give the title compound (41 mg,100%) as a clear, colorless residue. The material was used in the nextstep without further purification. LCMS, [M + H]⁺ = 493.4.

Example 112

To a solution of 112A (41 mg, 0.083 mmol) in THF (0.56 mL) was added 1.0M aq. LiOH (0.42 mL, 0.42 mmol). The reaction was stirred at RT for 23h, then was concentrated in vacuo. The residue was dissolved in 1:1MeCN:H₂O (1.5 mL) and TFA was added to adjust the pH to 3. This materialwas purified by preparative HPLC (Column: Sunfire Prep C18 OBD, 30 x 100mm, 5-µm particles; Mobile Phase A: 10:90 MeCN:H₂O with 0.1% TFA; MobilePhase B: 90:10 MeCN:H₂O with 0.1% TFA; Gradient: 10-100% B over 10 min,then a 2-min hold at 100% B; Flow: 40 mL/min) to give the title compound(10 mg, 20%) as a white solid. LCMS, [M + H]⁺ = 479.4. ¹H NMR (500 MHz,DMSO-d₆ and D₂O) δ 7.90 (d, J=8.5 Hz, 1H), 7.59 (br d, J=8.5 Hz, 1H),7.30 - 7.25 (m, 2H), 7.23 - 7.16 (m, 3H), 4.81 (br s, 1H), 4.64 (s, 2H),4.18 (s, 2H), 4.13 (s, 3H), 2.67 - 2.59 (m, 1H), 2.49 (s, 3H), 2.07 -1.98 (m, 1H), 1.91 - 1.74 (m, 3H), 1.68 - 1.44 (m, 4H). hLPA₁ IC₅₀ = 63nM.

Example 113.(1S,3S)-3-((6-(5-((3-benzyl-1-methylureido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methyl-pyridin-3-yl)oxy)cyclohexane-1-carboxylicacid, TFA salt.

113A. Methyl(1S,3S)-3-((2-methyl-6-(1-methyl-5-((methylamino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a RT solution of aldehyde Example 64A (325 mg, 0.91 mmol) in MeOH(3.6 mL) was added MeNH₂.HCl (92 mg, 1.36 mmol). The reaction wasstirred at RT for 20 min, then NaBH₃CN (85 mg, 1.36 mmol) was added. Thereaction was stirred at RT for 2 h, then was partitioned between EtOAcand 1.0 M aq. K₂HPO₄. The aqueous layer was extracted with EtOAc (2x).The combined organic extracts were washed with brine, dried (Na₂SO₄) andconcentrated in vacuo to give a viscous yellow oil. The residue waschromatographed (SiO₂; continuous gradient from 0-10% MeOH/CH₂Cl₂) togive the title compound (180 mg, 53%) as a clear, colorless oil. LCMS,[M+H]⁺ = 374.2. ¹H NMR (500 MHz, CD₃OD) δ 7.89 (d, J=8.8 Hz, 1H), 7.47(d, J=8.5 Hz, 1H), 4.84 - 4.79 (m, 1H), 4.16 (s, 3H), 4.09 (s, 2H), 3.70(s, 3H), 2.89 - 2.82 (m, 1H), 2.53 (s, 3H), 2.46 (s, 3H), 2.19 - 2.09(m, 1H), 2.01 - 1.90 (m, 3H), 1.82 - 1.61 (m, 4H).

113B. Methyl(1S,3S)-3-((6-(5-((3-benzyl-1-methylureido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a 0° C. solution of 113A (20 mg, 0.054 mmol) in DCE (1.1 mL) wasadded Et₃N (52 µL, 0.38 mmol) followed by triphosgene (24 mg, 0.080mmol). The reaction was stirred at 0° C. for 30 min; benzylamine (35 µL,0.32 mmol) was then added. The reaction was allowed to warm to RT (awhite precipitate formed over time) and stirred at RT for 1 h. Thereaction mixture was partitioned between EtOAc and 0.5 M aq. HCl. Theaqueous layer was extracted with EtOAc (2x). The combined organicextracts were washed with 1.0 M aq. K₂HPO₄ and brine, dried (Na₂SO₄) andconcentrated in vacuo to give the title compound (27 mg, 100%) as aclear, pale yellow oil. This material was used in the next step withoutfurther purification. LCMS, [M + H]⁺ = 507.4.

Example 113

To a solution of 113B (27 mg, 0.053 mmol) in THF (0.36 mL) was added 1.0M aq. LiOH (0.27 mL, 0.27 mmol). The reaction was stirred at RT for 18.5h, then was partitioned between water and EtOAc. The aqueous layer wasextracted with EtOAc (2x) and these combined organic extracts werediscarded. The aqueous layer was acidified with 1 N aq. HCl to pH 5 andthen extracted with EtOAc (3x). These combined organic extracts werewashed with brine, dried (Na₂SO₄) and concentrated in vacuo.Purification by preparative HPLC (Column: Sunfire Prep C18 OBD, 30 x 100mm, 5-µm particles; Mobile Phase A: 10:90 MeCN:H₂O with 0.1% TFA; MobilePhase B: 90:10 MeCN:H₂O with 0.1% TFA; Gradient: 15-100% B over 10 min,then a 2-min hold at 100% B; Flow: 40 mL/min) gave the title compound (8mg, 25%) as a white solid. LCMS, [M + H]⁺ = 493.3. ¹H NMR (400 MHz,DMSO-d₆) δ 7.86 (d, J=8.6 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.33 - 7.26(m, 2H), 7.26 - 7.13 (m, 4H), 5.13 (s, 2H), 4.82 - 4.74 (m, 1H), 4.27(d, J=5.5 Hz, 2H), 3.99 (s, 3H), 2.83 (s, 3H), 2.71 - 2.58 (m, 1H), 2.43(s, 3H), 2.09 - 1.97 (m, 1H), 1.92 - 1.74 (m, 3H), 1.70 - 1.44 (m, 4H).31 of 32 protons found, missing the acid proton. hLPA₁ IC₅₀= 218 nM.

The examples in Table 5 below were synthesized according to theprocedures described for the preparation of Examples 112 and 113.

TABLE 5 Ex # Structure & Name Analytical & Biology Data Method 114

LCMS, [M + H]⁺ = 471.3; ¹H NMR (500 MHz, DMSO-d₆ and D₂O) δ 7.96 (d,J=8.8 Hz, 1H), 7.75 (br d, J=7.4 Hz, 1H), 4.87 (br s, 1H), 4.55 (s, 2H),4.11 (s, 3H), 3.25 - 3.17 (m, 2H), 2.77 (s, 3H), 2.68 - 2.59 (m, 1H),2.54 (s, 3H), 2.09 - 1.99 (m, 1H), 1.92 - 1.75 (m, 3H), 1.70 - 1.44 (m,4H), 1.25 (q, J=7.2 Hz, 2H), 0.56 - 0.45 (m, 1H), 0.31 - 0.24 (m, 2H),-0.05 - -0.13 (m, 2H); hLPA₁ IC₅₀ = 112 nM. Example 112 115

LCMS, [M + H]⁺ = 507.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (d, J=8.5 Hz,1H), 7.50 (d, J=8.5 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.27 - 7.22 (m, 1H),7.20 - 7.16 (m, 2H), 4.91 (s, 2H), 4.81 - 4.74 (m, 1H), 4.28 (s, 2H),4.01 (s, 3H), 2.74 (s, 3H), 2.68 -2.59 (m, 1H), 2.58 (s, 3H), 2.45 (s,3H), 2.06 - 1.97 (m, 1H), 1.91 - 1.74 (m, 3H), 1.68 - 1.45 (m, 4H).Missing the acid proton; Example 113

hLPA₁ IC₅₀ = 166 nM. 116

LCMS, [M + H]⁺ = 473.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.91 (d, J=8.5 Hz,1H), 7.60 (br d, J=8.5 Hz, 1H), 4.81 (br s, 1H), 4.56 (s, 2H), 4.10 (s,3H), 3.16 - 3.06 (m, 2H), 2.72 (s, 3H), 2.68 - 2.58 (m, 1H), 2.50 (s,3H), 2.10 - 1.96 (m, 1H), 1.94 - 1.74 (m, 3H), 1.69 - 1.43 (m, 4H),1.41 - 1.29 (m, 1H), 1.23 - 1.11 (m, 2H), 0.75 (d, J=6.4 Hz, 6H). 34 of36 protons found; hLPA₁ IC₅₀ = 92 nM. Example 112 117

LCMS, [M + H]⁺ = 483.4; ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 - 7.82 (m,J=8.5 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H), 4.75 (br s, 1H), 4.70 - 4.59 (m,2H), 4.09 (s, 3H), 3.80 - 3.67 (m, 1H), 2.66 - 2.57 (m, 1H), 2.48 (s,3H), 2.20 - 2.11 (m, 1H), 2.09 - 1.93 (m, 2H), 1.89 - 1.74 (m, 4H), 1.70-1.37 (m, 6H), 1.34 - 1.14 (m, 3H), 1.14 - 1.02 (m, 1H), 0.68 -0.51 (m,1H). 31 of 34 protons found; hLPA₁1 IC₅₀ = 420 nM. Example 112 118

LCMS, [M + H]⁺ = 459.4; ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (d, J=8.5 Hz,1H), 7.48 (d, J=8.5 Hz, 1H), 4.78 (br s, 1H), 4.65 - 4.55 (m, 2H), 4.09(s, 3H), 2.92 - 2.84 (m, 1H), 2.80 -2.72 (m, 1H), 2.66 - 2.57 (m, 1H),2.47 (s, 3H), 2.06 - 1.95 (m, 1H), 1.93 - 1.72 (m, 3H), 1.68 -1.40 (m,4H), 1.37 - 1.11 (m, 2H), 1.02 - 0.88 (m, 1H), 0.82 -0.66 (m, 6H). 31 of34 protons found; hLPA₁ IC₅₀ = 105 nM. Example 112 119

LCMS, [M + H]⁺ = 521.5; ¹H NMR (500 MHz, DMSO-d₆) δ 7.86 (d, J=8.5 Hz,1H), 7.52 (d, J=8.9 Hz, 1H), 7.28 - 7.13 (m, 5H), 4.79 (br s, 1H), 4.66-4.51 (m, 3H), 4.08 - 3.99 (m, 3H), 2.67 - 2.57 (m, 1H), 2.47 (s, 3H),2.07 - 1.96 (m, 1H), 1.90 -1.72 (m, 3H), 1.68 - 1.42 (m, 6H), 1.23 -1.04 (m, 2H), 0.78 (br t, J=7.3 Hz, 3H). 33 of 36 protons found; hLPA₁IC₅₀ = 187 nM. Example 112 120

LCMS, [M + H]⁺ = 507.4; ¹H NMR (500 MHz, DMSO-d₆) δ 7.89 (d, J=8.5 Hz,1H), 7.56 (br d, J=8.5 Hz, 1H), 7.30 - 7.24 (m, 2H), 7.19 (br d, J=6.7Hz, 3H), 4.81 (br s, 1H), 4.61 (br s, 2H), 4.53 - 4.44 (m, 1H), 4.06 (s,3H), 2.67 - 2.60 (m, 1H), 2.09 -1.98 (m, 1H), 1.92 - 1.74 (m, 3H),1.69 - 1.44 (m, 6H), 0.74 (br t, J=7.2 Hz, 3H). 28 of 34 protons found;hLPA₁ IC₅₀ = 238 nM. Example 112 121

LCMS, [M + H]⁺ = 511.4; ¹H NMR (500 MHz, DMSO-d₆) δ 7.93 - 7.84 (m, 1H),7.57 - 7.49 (m, 1H), 7.33 - 7.23 (m, 5H), 5.00 - 4.86 (m, 1H), 4.79 (brs, 1H), 4.68 - 4.37 (m, 4H), 3.89 -3.71 (m, 3H), 2.66 - 2.58 (m, 1H),2.48 (s, 3H), 2.07 - 1.95 (m, 1H), 1.93 - 1.71 (m, 3H), 1.68 -1.41 (m,4H). 28 of 31 protons found; hLPA₁ IC₅₀ = 555 nM. Example 112 122

LCMS, [M + H]⁺ = 459.4; ¹H NMR (500 MHz, DMSO-d₆) δ 7.90 (br d, J=8.9Hz, 1H), 7.61 (br d, J=8.5 Hz, 1H), 4.82 (br s, 1H), 4.59 (s, 2H), 4.10(s, 3H), 2.96 (br t, J=7.2 Hz, 2H), 2.62 (br t, J=10.4 Hz, 1H), 2.07 -1.98 (m, 1H), 1.92 - 1.73 (m, 3H), 1.71 - 1.41 (m, 5H), 1.24 - 1.14 (m,2H), 0.80 (d, J=6.4 Hz, 6H). 28 of 34 protons found; hLPA₁ IC₅₀ = 101nM. Example 112 123

LCMS, [M + H]⁺ = 493.4; ¹H NMR (500 MHz, DMSO-d₆) δ 7.92 (d, J=8.5 Hz,1H), 7.65 (br d, J=8.9 Hz, 1H), 4.83 (br s, 1H), 4.59 (s, 2H), 4.09 (s,3H), 3.11 - 3.04 (m, 1H), 2.67 - 2.58 (m, 1H), 2.26 - 2.11 (m, 3H),2.07 - 1.98 (m, 1H), 1.93 - 1.73 (m, 3H), 1.67 - 1.43 (m, 4H). 21 of 30protons found; hLPA₁ IC₅₀ = 929 nM. Example 112 124

LCMS, [M + H]⁺ = 445.4; ¹H NMR (500 MHz, DMSO-d₆) δ 7.90 (br d, J=8.5Hz, 1H), 7.61 (br d, J=8.9 Hz, 1H), 4.82 (br s, 1H), 4.59 (s, 2H), 4.10(s, 3H), 2.95 (br t, J=6.7 Hz, 2H), 2.73 -2.58 (m, 1H), 2.07 - 1.97 (m,1H), 1.92 - 1.73 (m, 3H), 1.69 -1.42 (m, 4H), 1.34 - 1.24 (m, 2H),1.24 - 1.13 (m, 2H), 0.80 (t, J=7.2 Hz, 3H). 26 of 32 protons found;hLPA₁ IC₅₀ = 434 nM. Example 112 125

LCMS, [M + H]⁺ = 473.4; ¹H NMR (500 MHz, DMSO-d₆) δ 7.91 (d, J=8.5 Hz,1H), 7.60 (br d, J=8.5 Hz, 1H), 4.82 (br s, 1H), 4.64 - 4.54 (m, 2H),4.10 (s, 3H), 2.97 - 2.87 (m, 1H), 2.68 -2.59 (m, 1H), 2.56 (br s, 3H),2.09 - 1.97 (m, 1H), 1.93 - 1.74 (m, 3H), 1.68 - 1.45 (m, 5H), 0.96 (d,J=6.7 Hz, 3H), 0.81 (d, J=6.4 Hz, 3H), 0.57 (br d, J=6.4 Hz, 3H). 31 of36 protons found; hLPA₁ IC₅₀ = 1,206 nM. Example 112 126

LCMS, [M + H]⁺ = 459.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.88 (d, J=8.5 Hz,1H), 7.54 (d, J=8.9 Hz, 1H), 4.80 (br s, 1H), 4.68 - 4.59 (m, 2H), 4.11(s, 3H), 2.97 - 2.88 (m, 1H), 2.67 -2.59 (m, 1H), 2.50 (br s, 3H),2.09 - 1.97 (m, 1H), 1.93 - 1.70 (m, 3H), 1.70 - 1.42 (m, 5H), 0.89 (d,J=6.7 Hz, 3H), 0.76 (d, J=6.7 Hz, 6H). 31 of 34 protons found; hLPA₁IC₅₀ = 611 nM. Example 112 127

LCMS, [M + H]⁺ = 445.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (d, J=8.5 Hz,1H), 7.53 (d, J=8.9 Hz, 1H), 4.80 (br s, 1H), 4.62 (s, 2H), 4.11 (s,3H), 2.81 - 2.75 (m, 2H), 2.66 - 2.58 (m, 1H), 2.50 (br s, 3H), 2.06-1.99 (m, 1H), 1.93 - 1.72 (m, 3H), 1.69 - 1.43 (m, 5H), 0.76 (d, J=6.7Hz, 6H). 29 of 32 protons found; hLPA₁ IC₅₀ = 2,270 nM. Example 112 128

LCMS, [M + H]⁺ = 459.3; ¹H NMR (500 MHz, DMSO-d6) δ 7.87 (d, J=8.5 Hz,1H), 7.52 (d, J=8.5 Hz, 1H), 6.71 (br t, J=5.8 Hz, 1H), 4.79 (br s, 1H),4.58 (br d, J=5.8 Hz, 2H), 4.10 (s, 3H), 2.93 (br d, J=7.3 Hz, 2H), 2.73(s, 3H), 2.67 - 2.58 (m, 1H), 2.48 (s, 3H), 2.06 - 1.97 (m, 1H), 1.92 -1.69 (m, 4H), 1.67 -1.44 (m, 4H), 0.68 (d, J=6.4 Hz, 6H). 33 of 34protons found; hLPA₁ IC₅₀ = 273 nM. Example 112 129

LCMS, [M + H]⁺ = 493.4; ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (d, J=8.6 Hz,1H), 7.51 (d, J=8.7 Hz, 1H), 7.31 - 7.16 (m, 5H), 4.81 - 4.70 (m, 2H),4.70 - 4.59 (m, 2H), 4.08 (s, 3H), 2.70 - 2.61 (m, 1H), 2.49 (s, 3H),2.08 - 1.98 (m, 1H), 1.94 - 1.77 (m, 3H), 1.73 - 1.48 (m, 4H), 1.29 (d,J=7.0 Hz, 3H). 29 of 32 protons found; hLPA₁ IC₅₀ = 142 nM. Example 112130

LCMS, [M + H]⁺ = 493.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.89 (d, J=8.5 Hz,1H), 7.58 (br d, J=8.9 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.24 - 7.14 (m,3H), 4.81 (br s, 1H), 4.74 - 4.65 (m, 1H), 4.64 - 4.54 (m, 2H), 4.07 (s,3H), 2.67 - 2.59 (m, 1H), 2.50 (s, 3H), 2.07 - 1.97 (m, 1H), 1.92 -1.73(m, 3H), 1.69 - 1.45 (m, 4H), 1.26 (d, J=7.0 Hz, 3H). 29 of 32 protonsfound; hLPA₁ IC₅₀ = 275 nM. Example 112 131

LCMS, [M + H]⁺ = 507.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (d, J=8.9 Hz,1H), 7.49 (d, J=8.9 Hz, 1H), 7.28 - 7.24 (m, 2H), 7.21 - 7.18 (m, 1H),7.12 (br d, J=7.6 Hz, 2H), 6.89 (br t, J=5.6 Hz, 1H), 5.43 - 5.37 (m,1H), 4.77 (br s, 1H), 4.73 -4.60 (m, 2H), 4.11 (s, 3H), 2.68 -2.57 (m,1H), 2.47 (s, 3H), 2.41 (s, 3H), 2.05 - 1.94 (m, 1H), 1.91 - 1.69 (m,3H), 1.69 - 1.42 (m, 4H), 1.36 (d, J=7.0 Hz, 3H). 33 of 34 protonsfound; hLPA₁ IC₅₀ = 217 nM. Example 112 132

LCMS, [M + H]⁺ = 507.4; ¹H NMR (500 MHz, CDCl₃) δ 8.16 (d, J=9.1 Hz,1H), 7.80 (br d, J=8.8 Hz, 1H), 7.36 -7.30 (m, 2H), 7.28 - 7.22 (m, 3H),5.69 - 5.54 (m, 1H), 4.85 - 4.75 (m, 1H), 4.68 (s, 2H), 4.27 (s, 3H),2.92 - 2.81 (m, 1H), 2.70 (s, 3H), 2.68 (s, 3H), 2.22 - 2.10 (m, 1H),2.00 - 1.77 (m, 6H), 1.72 - 1.61 (m, 1H), 1.51 (d, J=7.2 Hz, 3H). 32 of34 protons found; hLPA₁ IC₅₀ = 276 nM. Example 112 133

LCMS, [M + H]⁺ = 459.0; ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (br d, J=8.005Hz, 1H), 7.51 (br d, J=8.7 Hz, 1H), 6.60 (br s, 1H), 4.77 (br s, 1H),4.67 - 4.55 (m, 2H), 4.18 - 4.03 (m, 3H), 2.76 - 2.67 (m, 3H), 2.67 -2.58 (m, 1H), 2.48 (s, 3H), 2.05 - 1.95 (m, 1H), 1.89 - 1.75 (m, 3H),1.71 - 1.48 (m, 4H), 1.28 (s, 6H). 30 of 34 protons; hLPA₁ IC₅₀ = 1,089nM Example 112 134

LCMS, [M + H]⁺ = 445.4; ¹H NMR (500 MHz, DMSO-d₆) δ 7.88 (d, J=8.5 Hz,1H), 7.54 (d, J=8.5 Hz, 1H), 4.79 (br s, 1H), 4.56 (s, 2H), 4.24 - 4.18(m, 1H), 4.10 (s, 3H), 2.67 - 2.59 (m, 1H), 2.57 (s, 3H), 2.48 (s, 3H),2.05 - 1.99 (m, 1H), 1.92 - 1.73 (m, 3H), 1.67 - 1.42 (m, 4H), 0.94 (d,J=6.7 Hz, 6H). 30 of 32 protons found; hLPA₁ IC₅₀ = 519 nM Example 112

Example 135.(1S,3S)-3-((6-(5-(3-benzylureido)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylicacid, 1TFA.

135A. Methyl(1S,3S)-3-((6-(5-(3-benzylureido)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate,1TFA

To a microwave vial containing a suspension of Example 64B (30 mg, 0.080mmol) in toluene (0.80 mL) was added Et₃N (67 µL, 0.48 mmol) and(PhO)₂PON₃ (43 µL, 0.20 mmol). The reaction was heated in a microwavereactor at 100° C. for 1 h, then was cooled to RT. Benzylamine (22 µL,0.20 mmol) was added and the reaction was heated in a microwave reactorat 100° C. for 10 min, then was cooled to RT. The reaction mixture waspartitioned between EtOAc and 1.0 M aq. K₂HPO₄. The aqueous layer wasextracted with EtOAc (2x). The combined organic extracts were dried(Na₂SO₄) and concentrated in vacuo. The clear, colorless residue waspurified by preparative HPLC (Column: Sunfire Prep C18 OBD, 30 x 100 mm,5-µm particles; Mobile Phase A: 10:90 MeOH:H₂O with 0.1% TFA; MobilePhase B: 90:10 MeOH:H₂O with 0.1% TFA; Gradient: 25-100% B over 10 min,then a 2-min hold at 100% B; Flow: 40 mL/min.) to give the titlecompound (22 mg, 46%) as a clear, colorless oil. LCMS, [M + H]⁺ = 479.3.

Example 135

To a solution of 135A (22 mg, 0.037 mmol) in THF (0.24 mL) was added aq.1.0 M LiOH (0.22 mL, 0.22 mmol). The reaction was stirred at RT for 20h, then was concentrated in vacuo. The residue was dissolved in 1:1MeCN:H₂O (1.5 mL); TFA was added to adjust the pH to 3. This materialwas purified by preparative HPLC (Column: Sunfire Prep C18 OBD, 30 x 100mm, 5-µm particles; Mobile Phase A: 10:90 MeCN:H₂O with 0.1% TFA; MobilePhase B: 90:10 MeCN:H₂O with 0.1% TFA; Gradient: 10-100% B over 10 min,then a 2-min hold at 100% B; Flow: 40 mL/min) to give the title compound(13 mg, 61%) as a white solid. LCMS, [M + H]⁺ = 465.3. ¹H NMR (500 MHz,CDCl₃) δ 11.59 - 11.45 (m, 1H), 9.76 - 9.66 (m, 1H), 8.16 (d, J=8.8 Hz,1H), 7.92 (d, J=9.1 Hz, 1H), 7.42 - 7.38 (m, 2H), 7.38 - 7.32 (m, 2H),7.31 - 7.26 (m, 1H), 4.76 - 4.67 (m, 1H), 4.53 (br d, J=5.0 Hz, 2H),4.11 (s, 3H), 2.89 - 2.82 (m, 1H), 2.26 (s, 3H), 2.23 - 2.15 (m, 1H),2.06 - 1.93 (m, 2H), 1.86 - 1.63 (m, 4H), 1.63 - 1.52 (m, 1H). 27 of 28protons found, missing the acid proton. hLPA₁ IC₅₀ = 329 nM.

Example 136.(1S,3S)-3-((2-methyl-6-(1-methyl-5-(3-((R)-1-phenylethyl)ureido)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid, 1TFA

Example 136 was synthesize according to the procedures described for thepreparation of Example 135. LCMS, [M + H]⁺ = 479.1; ¹H NMR (500 MHz,DMSO-d₆) δ 8.48 (s, 1H), 7.80 (br d, J=7.9 Hz, 1H), 7.73 (br d, J=8.5Hz, 1H), 7.51 (br d, J=8.5 Hz, 1H), 7.39 - 7.26 (m, 4H), 7.25 - 7.19 (m,1H), 4.86 - 4.73 (m, 2H), 3.84 (s, 3H), 2.69 -2.59 (m, 1H), 2.54 (s,3H), 2.11 - 1.95 (m, 1H), 1.92 - 1.72 (m, 3H), 1.70 - 1.44 (m, 4H), 1.39(br d, J=7.0 Hz, 3H); carboxylic acid proton not observed. hLPA₁ IC₅₀ =103 nM.

Example 137.(1S,3S)-3-((6-(5-(((N-(cyclopentylmethyl)-N-methylsulfamoyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylicacid

137A. (cyclopentylmethyl)(methyl)sulfamoyl Chloride

To a 0° C. solution of 1.0 M sulfuryl chloride in CH₂Cl₂ (514 µL, 0.51mmol) in CH₂Cl₂ (1 mL) was added a mixture of1-cyclopentyl-N-methylmethanamine-HCl salt (77 mg, 0.51 mmol) and TEA(179 µL, 1.29 mmol) in CH₂Cl₂ (1 mL). The reaction mixture was allowedto warm to RT and stirred at RT for 2 h to give the crude titlecompound, which was used in the next reaction without furtherpurification.

137B. Tert-butyl(1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methyl-pyridin-3-yl)oxy)cyclohexane-1-carboxylate

A mixture of(1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methyl-pyridin-3-yl)oxy)cyclohexane-1-carboxylicacid (from LiOH-mediated hydrolysis of 1E; 500 mg, 1.44 mmol) andtert-butyl (Z)-N,N′-diisopropylcarbamimidate (867 mg, 4.33 mmol) intert-butyl alcohol (1 mL)/THF (1 mL) was stirred at RT for 18 h. Thereaction was filtered; the filtrate was concentrated in vacuo. The crudeoily product was purified by preparative HPLC (Sunfire C18 30 x 100mm-regenerated column; detection at 220 nm; flow rate = 40 mL/min;continuous gradient from 20% B to 100% B over 10 min + 2 min hold timeat 100% B, where A = 90:10 H₂O:MeCN and B = 90:10 MeCN:H₂O) to give thetitle compound (300 mg, 0.745 mmol, 51.6 % yield) as clear oil. [M + H]⁺= 403.2

137C. Tert-butyl(1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methyl-pyridin-3-yl)oxy)cyclohexane-1-carboxylate

A mixture of 137B (300 mg, 0.75 mmol), DBU (0.23 mL, 1.49 mmol) and(PhO)₂PON₃ (0.24 mL, 1.12 mmol) in THF (5 mL) was stirred at RTovernight. Ph₃P (391 mg, 1.49 mmol) and H₂O (1 mL) were added, and thereaction mixture was stirred at RT for 2 h, then was partitioned betweenEtOAc and water. The organic layer was washed with brine, dried(Na₂SO₄), and concentrated in vacuo. The crude oil was chromatographed(24 g SiO₂; continuous gradient from 0-10% EtOAc/Hexane over 10 min) togive the title compound (280 mg, 0.697 mmol, 94% yield) as clear oil.[M + H]⁺ = 402.2

Example 137

137A (21 mg, 0.10 mmol) was added to a solution of 137C (20 mg, 0.050mmol) and iPr₂NEt (0.026 mL, 0.149 mmol) in DCM (1 mL) at 0° C. over 5min. The reaction was stirred at RT for 20 h, after which TFA (0.5 mL)was added. The reaction was stirred at RT for 2 h, then was concentratedin vacuo. The crude product was purified by preparative HPLC (SunfireC18 30 x 100 mm-regenerated column; detection at 220 nm; flow rate = 40mL/min; continuous gradient from 30% B to 100% B over 10 min + 2 minhold time at 100% B, where A = 90:10:0.1 H₂O:MeCN:TFA and B = 90:10:0.1MeCN:H₂O:TFA) to give the title compound (TFA salt; 4 mg, 6.0 µmol, 12%yield) as a yellowish oil. ¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, J=8.8 Hz,1H), 7.53 (d, J=8.8 Hz, 1H), 4.77 (br d, J=1.3 Hz, 1H), 4.42 (s, 2H),4.15 (s, 3H), 3.01 (d, J=7.7 Hz, 2H), 2.93 -2.82 (m, 1H), 2.75 (s, 3H),2.62 (s, 3H), 2.15 - 1.49 (m, 16H), 1.24 - 1.15 (m, 2H); LCMS, [M + H]⁺= 521.3; hLPA₁ IC₅₀ = 167 nM

The following examples in Table 6 were synthesized according to theprocedures described for the preparation of Example 136.

TABLE 6 Ex # Structure & Name Analytical & Biological Data 138

LCMS, [M+H]+ = 495.2; ¹H NMR (500 MHz, CDCl₃) δ 8.03 (d, J=8.8 Hz, 1H),7.80 (br d, J=8.8 Hz, 1H), 4.85 (br s, 1H), 4.48 (s, 2H), 4.18 (s, 3H),3.15 - 3.08 (m, 2H), 2.91 (br d, J=3.9 Hz, 1H), 2.78 (s, 3H), 2.73 (s,3H), 2.20 - 1.64 (m, 9H), 1.58 - 1.49 (m, 2H), 1.32 (dq, J=14.9, 7.4 Hz,2H), 0.93 (t, J=7.3 Hz, 3H); hLPA₁ IC₅₀ = 449 nM. 139

LCMS, [M+H]+ = 529.2; ¹H NMR (400 MHz, CDCl3) δ 7.99 (d, J=8.8 Hz, 1H),7.58 (br d, J=8.6 Hz, 1H), 7.39 - 7.26 (m, 5H), 4.77 (br d, J=2.4 Hz,1H), 4.45 (s, 2H), 4.25 (s, 2H), 4.11 (s, 3H), 2.87 (br s, 1H), 2.66 (s,3H), 2.63 (s, 3H), 2.10 - 2.03 (m, 2H), 1.99 - 1.59 (m, 6H); hLPA₁ IC₅₀= 313 nM.

The following examples in Table 7 below were synthesized according tothe procedures described for the preparation of Example 64.

TABLE 7 Ex # Structure & Name Analytical&Biology Data 140

LCMS, [M + H]⁺ = 446.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 - 7.63 (m, 1H),7.50 - 7.39 (m, 1H), 4.87 - 4.61 (m, 2H), 3.94 -3.79 (m, 3H), 2.67 -2.51 (m, 5H), 2.43 - 2.30 (m, 3H), 2.11 - 1.95 (m, 1H), 1.91 - 1.70 (m,3H), 1.67 -0.73 (m, 12H); hLPA₁ IC₅₀ = 29 nM. 141

LCMS, [M + H]⁺ = 458.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.80 - 7.61 (m, 1H),7.53 - 7.35 (m, 1H), 4.84 - 4.66 (m, 1H), 4.61 -4.44 (m, 1H), 3.96 -3.76 (m, 3H), 3.70 - 3.45 (m, 1H), 2.67 - 2.51 (m, 5H), 2.44 - 2.29 (m,3H), 2.05 -1.02 (m, 15H); hLPA₁ IC₅₀ = 78 nM. 142

LCMS, [M + H]⁺ = 446.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.80 - 7.63 (m, 1H),7.54 - 7.42 (m, 1H), 4.93 - 4.70 (m, 1H), 4.61 -4.45 (m, 1H), 3.94 -3.76 (m, 3H), 3.75 - 3.48 (m, 1H), 2.66 - 2.52 (m, 5H), 2.44 - 2.31 (m,3H), 2.07 -1.72 (m, 4H), 1.69 - 1.27 (m, 6H), 1.14 - 0.51 (m, 5H); hLPA₁IC₅₀ = 30 nM. 143

LCMS, [M + H]⁺ = 436.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.81 - 7.66 (m, 1H),7.53 - 7.34 (m, 1H), 4.91 - 4.70 (m, 2H), 4.34 -4.04 (m, 2H), 3.93 -3.83 (m, 3H), 2.63 - 2.53 (m, 3H), 2.44 - 2.36 (m, 3H), 1.99 - 1.73 (m,4H), 1.71 -1.43 (m, 4H), 1.37 - 1.12 (m, 3H); hLPA₁ IC₅₀= 478 nM. 144

LCMS, [M + H]⁺ = 436.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.81 - 7.65 (m, 1H),7.48 - 7.34 (m, 1H), 4.85 - 4.66 (m, 1H), 4.25 -4.06 (m, 1H), 3.99 -3.80 (m, 3H), 3.63 - 3.36 (m, 3H), 2.68 - 2.53 (m, 4H), 2.43 - 2.33 (m,3H), 2.06 -1.39 (m, 9H); hLPA₁ IC₅₀= 254 nM. 145

LCMS, [M + H]⁺ = 472.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 - 7.66 (m, 1H),7.52 - 7.37 (m, 1H), 4.86 - 4.71 (m, 1H), 4.42 -4.06 (m, 2H), 3.93 -3.79 (m, 3H), 2.79 - 2.54 (m, 2H), 2.47 - 2.26 (m, 4H), 2.12 - 1.40 (m,9H); hLPA₁ IC₅₀ = 43 nM.

The following examples were synthesized according to the proceduresdescribed above.

TABLE 8 Ex # Structure & Name Analytical & Biology Data Method 146

LC-MS, [M+H]⁺ = 443.2; ¹H NMR (500 MHz, DMSO-d₆) 8.37 (s, 1H), 7.75 (d,J=8.5 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.20 (br d, J=8.0 Hz, 1H), 4.82 -4.74 (m, 1H), 3.87 (s, 3H), 3.30 - 3.18 (m, 1H), 2.68 - 2.60 (m, 1H),2.07 - 1.98 (m, 1H), 1.91 - 1.73 (m, 3H), 1.70 - 1.44 (m, 4H), 1.16 (d,J=6.9 Hz, 3H), 0.94 -0.82 (m, 1H), 0.46 - 0.33 (m, 2H), 0.33 - 0.25 (m,1H), 0.21 -0.11 (m, 1H). 26 of 30 protons found; methyl peak overlapswith DMSO-d₆ peak; hLPA₁ IC₅₀ = 306 nM. Example 135 147

LC-MS, [M+H]⁺ = 445.2; ¹H NMR (500 MHz, CD₃CN) δ 8.01 (d, J=8.8 Hz, 1H),7.73 (br d, J=8.8 Hz, 1H), 4.92 - 4.84 (m, 1H), 3.99 (s, 3H), 3.92 -3.82 (m, 1H), 2.84 - 2.76 (m, 1H), 2.60 (s, 3H), 2.16 - 2.07 (m, 1H),1.95 -1.86 (m, 3H), 1.82 - 1.35 (m, 8H), 1.20 (d, J=6.6 Hz, 3H), 0.95(t, J=7.3 Hz, 3H). 29 of 32 protons found; hLPA₁ IC₅₀= 517 nM. Example135 148

LCMS, [M+H]⁺ = 485.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.88 (d, J=8.6 Hz,1H), 7.55 -7.47 (m, 1H), 6.56 - 6.35 (m, 1H), 4.78 (br s, 1H), 4.69 (brd, J=5.4 Hz, 2H), 4.10 (s, 3H), 2.94 (br s, 1H), 2.87 (q, J=7.5 Hz, 2H),2.73 (s, 3H), 2.65 (br t, J=10.4 Hz, 1H), 2.47 - 2.27 (m, 2H), 2.04 (brd, J=14.1 Hz, 1H), 1.90 - 1.79 (m, 5H), 1.78 - 1.71 (m, 2H), 1.69 - 1.54(m, 6H), 1.35 - 1.26 (m, 3H); hLPA₁ IC₅₀ = 62 nM. Example 108 149

LC-MS, [M+H]⁺ = 507.4; ¹H NMR (500 MHz, DMSO-d₆) δ 8.01 - 7.78 (m, J=8.5Hz, 1H), 7.55 - 7.37 (m, J=8.6 Hz, 1H), 7.28 - 7.22 (m, 2H), 7.22 - 7.15(m, 1H), 7.09 (br d, J=7.3 Hz, 2H), 6.62 (br s, 1H), 4.75 (br d, J=5.5Hz, 3H), 4.40 (s, 2H), 4.10 (s, 3H), 2.83 - 2.68 (m, 5H), 2.63 (br s,1H), 2.14 - 1.96 (m, 1H), 1.92 (s, 2H), 1.84 (br d, J=13.8 Hz, 3H), 1.65(br s, 2H), 1.56 (br d, J=19.5 Hz, 2H), 1.28 - 1.19 (m, 3H); hLPA₁ IC₅₀= 143 nM Example 108 150

LC-MS, [M+H]⁺ = 473.5; ¹H NMR (500 MHz, DMSO-d₆) δ 7.93 - 7.80 (m, 1H),7.59 - 7.45 (m, 1H), 6.58 - 6.39 (m, 1H), 4.85 - 4.73 (m, 1H), 4.65 (brd, J=4.9 Hz, 2H), 4.08 (s, 3H), 3.09 (br t, J=7.3 Hz, 2H), 2.85 (q,J=7.3 Hz, 2H), 2.71 (s, 3H), 2.66 - 2.57 (m, 1H), 2.10 - 1.95 (m, 1H),1.88 - 1.75 (m, 3H), 1.71 -1.54 (m, 3H), 1.54 - 1.42 (m, 1H), 1.26 (brt, J=7.5 Hz, 5H), 1.14 - 1.06 (m, 2H), 0.76 (t, J=7.3 Hz, 3H); hLPA₁IC₅₀ = 44 nM Example 108 151

LC-MS, [M+H]⁺ = 459.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (d, J=8.5 Hz,1H), 7.50 (d, J=8.5 Hz, 1H), 6.29 - 6.20 (m, 1H), 6.16 - 6.13 (m, 1H),4.76 (br s, 1H), 4.68 (br d, J=5.8 Hz, 2H), 4.10 (s, 3H), 2.93 (q, J=6.4Hz, 2H), 2.86 (q, J=7.6 Hz, 2H), 2.03 - 1.88 (m, 1H), 1.83 - 1.76 (m,3H), 1.63 (br d, J=9.5 Hz, 2H), 1.53 (br d, J=12.2 Hz, 2H), 1.30 - 1.17(m, 9H), 0.81 (t, J=7.2 Hz, 3H); hLPA₁ IC₅₀ = 647 nM. Example 108 152

LC-MS, [M+H]⁺ = 471.4; ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J=8.5 Hz,1H), 7.61 (br d, J=8.5 Hz, 1H), 6.62 (br t, J=5.6 Hz, 1H), 4.72 - 4.62(m, 3H), 4.08 (s, 3H), 3.02 (d, J=6.7 Hz, 2H), 2.87 - 2.80 (m, 2H),2.80 - 2.73 (m, 3H), 1.94 (br s, 1H), 1.67 (br s, 3H), 1.63 - 1.54 (m,3H), 1.50 (br s, 1H), 1.26 (t, J=7.6 Hz, 3H), 0.78 (br d, J=6.4 Hz, 1H),0.33 (br d, J=7.6 Hz, 2H), 0.10 (br d, J=4.6 Hz, 2H); hLPA₁ IC₅₀ = 270nM. Example 108 153

LCMS, [M+H]+ = 493.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.89 (d, J=8.5 Hz,1H), 7.52 (d, J=8.5 Hz, 1H), 7.33 - 7.17 (m, 5H), 4.80 (br s, 1H), 4.74(s, 2H), 4.19 (br d, J=5.2 Hz, 2H), 4.13 (s, 3H), 2.88 (q, J=7.3 Hz,2H), 2.63 (br t, J=10.5 Hz, 1H), 2.04 (br d, J=13.4 Hz, 1H), 1.88 (br d,J=11.9 Hz, 1H), 1.85 -1.74 (m, 2H), 1.68 - 1.48 (m, 4H), 1.35 - 1.23 (m,3H); hLPA₁ IC₅₀ = 107 nM. Example 108

Intermediate 8. 4-Nitrophenyl (4-Oxopentyl) Carbonate

To a RT solution of 5-hydroxypentan-2-one (400 mg, 3.92 mmol) and4-nitrophenyl chloroformate (947 mg, 4.70 mmol) in THF (8 mL) was addedpyridine (0.95 mL, 11.8 mmol). The reaction mixture was stirred at RTfor 48 h; solids were filtered off and the filtrate was concentrated invacuo to give the crude product. This material was chromatographed (40 gSiO_(2;) continuous gradient from 0% to 50% EtOAc in hexanes in 12 min,then hold at 50% EtOAc in hexane for 10 min) to give the title compound(500 mg, 1.871 mmol, 47.8% yield) as a colorless oil. ¹H NMR (400 MHz,CDCl₃) δ 8.34 -8.21 (m, 2H), 7.40 - 7.33 (m, 2H), 4.31 (t, J= 6.3 Hz,2H), 2.62 (t, J= 7.0 Hz, 2H), 2.19 (s, 3H), 2.10 - 1.96 (m, 2H). LC-MS,[M+H]⁺ = 268.1.

The required 4-nitrophenyl carbonate intermediates for the preparationof the following examples were synthesized from the correspondingalcohols according to the procedure described for the preparation ofintermediate 2.

Intermediate # Structure & Name Analytical Data 9

¹H NMR (400 MHz, CDCl₃) δ 8.32 -8.24 (m, 2H), 7.42 - 7.34 (m, 2H), 4.29-4.14 (m, 2H), 2.45 - 2.26 (m, 2H), 2.17 -1.99 (m, 1H), 1.17 (d, J=6.2Hz, 3H). 10

LCMS, [M + H]⁺ = 276.0; ¹H NMR (400 MHz, CDCl₃) δ 8.29 (d, J= 9.1 Hz,2H), 7.38 (d, J = 9.0 Hz, 2H), 4.50 (t, J = 6.6 Hz, 2H), 2.36 (tt, J =15.6, 6.6 Hz, 2H), 1.70 (t, J = 18.6 Hz, 3H). 11

LCMS, [M + H]⁺ = 264.1; ¹H NMR (500 MHz, CDCl₃) δ 8.28 (dd, J = 9.0, 1.7Hz, 2H), 7.40 (d, J = 9.2 Hz, 2H), 5.29 (p, J = 7.0 Hz, 1H), 2.60 - 2.49(m, 2H), 2.49 - 2.35 (m, 2H), 0.52 (br s, 4H). 12

LCMS, [M + H]⁺ = 274.0; ¹H NMR (500 MHz, CDCl₃) δ 8.31 (d, J = 9.1 Hz,2H), 7.41 (d, J = 9.2 Hz, 2H), 5.07 (qtd, J = 7.6, 5.5, 3.4 Hz, 1H),3.15 (ddt, J = 15.6, 11.5, 7.1 Hz, 2H), 2.96 - 2.78 (m, 2H). 13

LCMS, [M + H]⁺ = 274.1; ¹H NMR (500 MHz, CDCl₃) δ 8.32 (d, J = 9.2 Hz,2H), 7.43 (d, J = 9.3 Hz, 2H), 4.46 -4.29 (m, 2H), 2.17 - 2.08 (m, 1H),1.66 (tdd, J = 11.5, 8.1, 4.8 Hz, 1H), 1.37 (dtd, J = 13.2, 7.7, 3.9 Hz,1H). 14

LCMS, [M + H]⁺ = 262.0; ¹H NMR (500 MHz, CDCl₃) δ 8.33 (d, J = 9.1 Hz,2H), 7.44 (d, J = 9.2 Hz, 2H), 4.45 (t, J = 11.8 Hz, 2H), 1.78 (t, J=18.6 Hz, 3H). 15

LCMS, [M + H]⁺ = 316.6; ¹H NMR (500 MHz, CDCl₃) δ 8.34 (d, J = 9.2 Hz,2H), 7.44 (d, J = 9.2 Hz, 2H), 4.76 (td, J = 12.4, 1.1 Hz, 2H). 16

LCMS, [M + H]⁺ = 290.1; ¹H NMR (500 MHz, CDCl₃) δ 8.32 (d, J = 9.2 Hz,2H), 7.42 (d, J = 9.2 Hz, 2H), 5.99 (tt, J = 56.4, 4.6 Hz, 1H), 4.22(qd, J = 10.7, 6.1 Hz, 2H), 2.29 (dq, J = 13.2, 6.6 Hz, 1H), 2.15 - 2.00(m, 1H), 1.93 -1.78 (m, 1H), 1.16 (d, J = 6.8 Hz, 3H) 17

LCMS, [M + H]⁺ = 266.1; ¹H NMR (400 MHz, CDCl₃) δ 8.28 (d, J = 9.2 Hz,2H), 7.38 (d, J = 9.2 Hz, 2H), 4.41 (t, J = 7.1 Hz, 2H), 1.70 (t, J =7.1Hz, 2H), 1.10 (s, 3H), 0.43 - 0.27 (m, 4H). 18

LCMS, [M + H]⁺ = 266.1; ¹H NMR (500 MHz, CDCl₃) δ 8.31 (d, J = 9.1 Hz,2H), 7.43 - 7.38 (m, 2H), 4.37 (dd, J = 10.4, 5.5 Hz, 1H), 4.19 (dd, J =10.4, 7.0 Hz, 1H), 1.25 - 1.15 (m, 1H), 1.12 (d, J = 6.6 Hz, 3H), 0.63(ddt, J = 13.6, 9.1, 4.3 Hz, 1H), 0.57 - 0.45 (m, 2H), 0.25 (ddd, J =10.2, 4.5, 1.8 Hz, 1H), 0.15 (ddd, J = 9.2, 4.8, 1.4 Hz, 1H). 19

LCMS, [M + H]⁺ = 252.1 ¹H NMR (500 MHz, CDCl₃) δ 8.31 (d, J = 9.1 Hz,2H), 7.41 (d, J = 9.1 Hz, 2H), 4.39 (t, J = 6.7 Hz, 2H), 1.69 (q, J =6.8 Hz, 2H), 0.88 - 0.73 (m, 1H), 0.62 - 0.47 (m, 2H), 0.16 (dt, J =6.0, 4.5 Hz, 2H). 20

¹H NMR (500 MHz, CDCl₃) δ 8.24 -8.17 (m, 2H), 7.37 - 7.27 (m, 3H), 7.14(d, J=7.7 Hz, 1H), 7.09 (dt, J=9.2, 1.9 Hz, 1H), 7.02 (td, J=8.4, 1.9Hz, 1H), 5.22 (s, 2H). 21

LCMS, [M + Na]⁺ = 276.0; ¹H NMR (500 MHz, CDCl₃) δ 8.30 (d, J = 9.1 Hz,2H), 7.41 (d, J = 9.2 Hz, 2H), 4.21 (dd, J = 10.4, 6.0 Hz, 1H), 4.12(dd, J = 10.4, 6.8 Hz, 1H), 1.87 (dddd, J = 12.4, 7.9, 6.8, 5.8 Hz, 1H),1.53 (dtd, J = 15.0, 7.5, 5.6 Hz, 1H), 1.36 - 1.23 (m, 1H), 1.03 (d, J =6.7 Hz, 3H), 0.98 (t, J = 7.5 Hz, 3H). 22

LCMS, [M + Na]⁺ = 280.1; ¹H NMR (500 MHz, CDCl₃) δ 8.29 (d, J= 9.2 Hz,2H), 7.40 (d, J= 9.1 Hz, 2H), 4.58 (t, J= 5.5 Hz, 1H), 4.49 (t, J= 5.7Hz, 1H), 4.37 (t, J= 6.2 Hz, 2H), 2.00 -1.79 (m, 4H). 23

LCMS, [M + Na]⁺ = 306.3; ¹H NMR (500 MHz, CDCl₃) δ 8.31 (d, J = 9.2 Hz,2H), 7.42 (d, J = 9.2 Hz, 2H), 4.69 (t, J = 5.9 Hz, 1H), 4.60 (t, J =6.0 Hz, 1H), 4.20 (s, 2H), 1.91 (t, J = 6.0 Hz, 1H), 1.86 (t, J = 6.0Hz, 1H), 0.73 -0.56 (m, 4H). 24

LCMS, [M + Na]⁺ = 287.9; ¹H NMR (500 MHz, CDCl₃) δ 8.10 (d, J =9.1 Hz,2H), 7.21 (d, J = 9.1 Hz, 2H), 4.25 (dd, J = 11.5, 7.0 Hz, 1H), 3.98(dd, J = 11.5, 8.9 Hz, 1H), 1.61 - 1.53 (m, 1H), 1.33 - 1.23 (m, 1H),0.97 (s, 3H), 0.94 (s, 3H), 0.88 (tdd, J = 8.8, 6.9, 5.3 Hz, 1H). 25

LCMS, [M + Na]⁺ = 276.0; ¹H NMR (500 MHz, CDCl₃) δ 8.30 (d, J = 9.2 Hz,2H), 7.41 (d, J = 9.1 Hz, 2H), 5.00 -4.85 (m, 1H), 1.77 (dddd, J = 13.0,9.9, 7.2, 5.5 Hz, 1H), 1.66 - 1.58 (m, 1H), 1.53 - 1.42 (m, 2H), 1.40(d, J = 6.3 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H). 26

¹H NMR (500 MHz, CDCl₃) δ 8.31 (d, J = 9.1 Hz, 2H), 7.41 (d, J = 9.2 Hz,2H), 4.35 (t, J = 6.3 Hz, 2H), 2.25 - 2.13 (m, 2H), 1.88 (dt, J = 9.0,6.4 Hz, 2H), 1.77 (tt, J = 10.6, 6.1 Hz, 2H). 27

LCMS, [M + H]⁺ = 252.0; ¹H NMR (400 MHz, CDCl₃) δ 8.30 (d, J = 9.2 Hz,2H), 7.41 (d, J = 9.2 Hz, 2H), 4.32 (dq, J = 8.8, 6.3 Hz, 1H), 1.49 (d,J = 6.3 Hz, 3H), 1.22 - 1.10 (m, 1H), 0.72 -0.61 (m, 2H), 0.61 - 0.51(m, 1H), 0.41 - 0.28 (m, 1H). 28

LCMS, [M + Na]⁺ = 276.0; ¹H NMR (500 MHz, CDCl₃) δ 8.30 (d, J = 9.1 Hz,2H), 7.41 (d, J = 9.2 Hz, 2H), 4.93 (dt, J = 7.3,6.0 Hz, 1H), 1.82 -1.71 (m, 1H), 1.62 (ddt, J = 13.8, 9.6, 5.9 Hz, 1H), 1.54 - 1.42 (m,2H), 1.40 (d, J = 6.3 Hz, 3H), 0.99 (t, J = 7.3 Hz, 3H). 29

LCMS, [M + H]⁺ = 252.1; ¹H NMR (500 MHz, CDCl₃) δ 8.31 (d, J = 9.1 Hz,2H), 7.42 (d, J =9.1 Hz, 2H), 4.15 (qd, J = 11.2, 7.5 Hz, 2H), 1.12 (d,J = 6.0 Hz, 3H), 1.00 (tq, J = 7.7, 4.5, 3.9 Hz, 1H), 0.87 - 0.78 (m,1H), 0.57 (dt, J = 9.0, 4.8 Hz, 1H), 0.45 (dt, J = 8.1, 5.1 Hz, 1H). 30

LCMS, [M + H]⁺ = 288.1; ¹H NMR (500 MHz, CDCl₃) δ 8.37 - 8.23 (m, 2H),7.48 - 7.36 (m, 2H), 4.38 (d, J= 6.7 Hz, 2H), 2.87 - 2.72 (m, 2H), 2.64(ddddd, J= 13.1, 10.8, 8.7, 5.3, 3.3 Hz, 1H), 2.57 - 2.40 (m, 2H). 31

LCMS, [M + Na]⁺ = 280.1; ¹H NMR (500 MHz, CDCl₃) δ 8.32 (d, J= 9.2 Hz,2H), 7.42 (d, J= 9.2 Hz, 2H), 4.55 (t, J= 6.3 Hz, 2H), 2.65 (qt, J=10.2, 6.3 Hz, 2H). 32

LCMS, [M + H]⁺ = 252.1; ¹H NMR (500 MHz, CDCl₃) δ 8.31 (d, J =9.1 Hz,2H), 7.42 (d, J = 9.1 Hz, 2H), 4.15 (qd, J = 11.2, 7.5 Hz, 2H), 1.12 (d,J = 6.0 Hz, 3H), 0.99 (tq, J = 7.9, 4.4, 3.9 Hz, 1H), 0.93 - 0.78 (m,1H), 0.57 (dt, J = 9.1, 4.8 Hz, 1H), 0.45 (dt, J = 8.2, 5.1 Hz, 1H). 33

LCMS, [M + H]⁺ = 252.0; ¹H NMR (500 MHz, CDCl₃) δ 8.38 - 8.19 (m, 2H),7.47 - 7.37 (m, 2H), 4.32 (dq, J = 8.9, 6.4 Hz, 1H), 1.49 (d, J = 6.3Hz, 3H), 1.16 (qt, J = 8.5, 4.9 Hz, 1H), 0.71 - 0.61 (m, 2H), 0.60 -0.53 (m, 1H), 0.35 (ddd, J = 10.2, 5.0, 3.8 Hz, 1H). 34

LCMS, [M + H]⁺ = 240.0; ¹H NMR (500 MHz, CDCl₃) δ 8.30 (d, J = 9.1 Hz,2H), 7.41 (d, J = 9.2 Hz, 2H), 4.87 (h, J = 6.3 Hz, 1H), 1.85 - 1.65 (m,2H), 1.40 (d, J = 6.2 Hz, 3H), 1.02 (t, J = 7.5 Hz, 3H). 35

LCMS, [M + Na]⁺ = 262.1; ¹H NMR (500 MHz, CDCl₃) δ 8.30 (d, J = 9.1 Hz,2H), 7.41 (d, J = 9.2 Hz, 2H), 4.86 (p, J = 6.3 Hz, 1H), 1.85 - 1.63 (m,2H), 1.40 (d, J = 6.3 Hz, 3H), 1.02 (t, J= 7.4 Hz, 3H). 36

LCMS, [M + H]⁺ = 254.1; ¹H NMR (500 MHz, CDCl₃) δ 8.30 (d, J = 9.2 Hz,2H), 7.41 (d, J = 9.1 Hz, 2H), 4.75 (p, J = 6.2 Hz, 1H), 2.02 - 1.90 (m,1H), 1.36 (d, J = 6.3 Hz, 3H), 1.02 (dd, J = 6.9, 3.0 Hz, 6H). 37

LCMS, [M + H]⁺ = 254.1; ¹H NMR (500 MHz, CDCl₃) δ 8.30 (d, J = 9.2 Hz,2H), 7.41 (d, J = 9.1 Hz, 2H), 4.75 (p, J = 6.2 Hz, 1H), 2.02 - 1.90 (m,1H), 1.36 (d, J = 6.3 Hz, 3H), 1.02 (dd, J = 6.9, 3.0 Hz, 6H). 38

LCMS, [M + H]⁺ = 294; ¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J = 9.2 Hz,2H), 7.41 (d, J = 9.2 Hz, 2H), 4.39 (t, J = 6.3 Hz, 2H), 2.38 - 2.23 (m,2H), 2.14 - 2.01 (m, 2H). 39

LCMS, [M + H]⁺ = 266; ¹H NMR (500 MHz, CDCl₃) δ 8.20 (d, J = 9.1 Hz,2H), 7.30 (d, J = 9.2 Hz, 1H), 5.01 (p, J = 7.3 Hz, 1H), 2.28 - 2.22 (m,2H), 1.96 (ddd, J = 10.1, 7.2, 2.9 Hz, 2H), 1.13 (s, 3H), 1.09 (s, 3H).

The examples in the following table were synthesized according to theprocedures described for the preparation of Examples 1 and 2 using the4-nitrophenyl carbonate intermediates above.

Ex # Structure & Name Analytical & Biological Data Method 154

LCMS, [M + H]⁺ = 501.4; ¹H NMR (500 MHz, DMSO-d₆) δ 8.64 (s, 2H), 7.59(s, 1H), 4.88 (s, 1H), 4.75 (d, J = 5.5 Hz, 2H), 4.08 (s, 3H), 3.83 (d,J = 6.1 Hz, 2H), 2.72 - 2.63 (m, 1H), 2.37 - 1.48 (m, 10H), 0.94 (d, J =6.6 Hz, 3H); hLPA₁ IC₅₀=2905 nM. Example 1 155

LCMS, [M + H]⁺= 515.3; ¹H NMR (500 MHz, DMSO-d₆) δ 8.59 (s, 1H), 7.60(s, 1H), 5.38 (s, 1H), 4.72 (d,J = 5.3 Hz, 2H), 4.05 (s, 3H), 3.82 (d, J= 6.2 Hz, 2H). 2.69 - 2.58 (m, 1H), 2.33 - 1.41 (m, 10H), 0.93 (d, J =6.6 Hz, 3H); hLPA₁ IC₅₀= 85 nM. Example 1 156

LCMS, [M + H]⁺ = 459.3; ¹H NMR (500 MHz, DMSO-d₆) δ 8.55 (s, 1H), 7.55(s, 1H), 5.39 (br s, 1H), 4.71 (d, J= 5.5 Hz, 2H), 4.07 (s, 3H), 3.91(d, J= 6.8 Hz, 2H), 2.69 - 2.59 (m, 1H), 2.47 (s, 3H), 2.14 - 1.42 (m,15H); hLPA₁ IC₅₀ = 213 nM. Example 1 157

LCMS, [M + H]⁺ = 458.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (d, J = 8.6 Hz,1H), 7.50 (br s, 1H), 7.47 (d, J= 8.6 Hz, 1H), 4.82 - 4.65 (m, 3H), 4.04(s, 3H), 3.98 (br s, 2H), 2.66 - 2.57 (m, 1H), 2.43 (s, 3H), 2.04 - 1.08(m, 10H), 0.64 (br s, 1H), 0.33 (br s, 2H), 0.0 (br s, 2H); hLPA₁ IC₅₀ =19 nM. Example 1 158

LCMS, [M + H]⁺ = 475.4; ¹H NMR (500 MHz, DMSO-d₆) δ 8.54 (s, 1H), 7.47(s, 1H), 5.38 (br s, 1H), 4.69 (br s, 2H), 4.05 (s, 3H), 4.0 -3.88 (m,2H), 2.67 - 2.57 (m, 1H), 2.46 (s, 3H), 2.12 - 1.37 (m, 10H), 0.85 (s,9H); hLPA₁ IC₅₀ = 76 nM. Example 1 159

LCMS, [M + H]⁺ = 498.9; ¹H NMR (500 MHz, DMSO-d₆) δ 8.55 (s, 1H), 7.74(s, 1H), 7.38 (d, J = 7.3 Hz, 1H), 7.12 (t, J = 10.3 Hz, 2H), 5.37 (s,1H), 5.02 (s, 2H), 4.79 -4.63 (m, 2H), 4.06 (s, 3H), 2.60 - 2.55 (m,1H), 2.44 (s, 3H), 2.10 - 1.36 (m, 8H); hLPA₁ IC₅₀ = 122 nM. Example 1160

LCMS, [M + H]⁺ = 459.0; ¹H NMR (500 MHz, DMSO-d₆) δ 8.54 (s, 1H), 7.50(s, 1H), 5.38 (s, 1H), 4.70 (d, J = 5.5 Hz, 2H), 4.06 (s, 3H), 3.97 (t,J = 6.7 Hz, 2H), 2.65 - 2.57 (m, 1H), 2.46 (s, 3H), 2.11 - 1.32 (m,10H), 0.64 (s, 1H), 0.34 (d, J = 7.9 Hz, 2H), 0.00 (d, J = 4.9 Hz, 2H);hLPA₁ IC₅₀= 66 nM. Example 1 161

LCMS, [M + H]⁺ = 460.9; ¹H NMR (500 MHz, DMSO-d₆) δ 8.54 (s, 1H), 7.51(s, 1H), 5.38 (s, 1H), 4.70 (s, 2H), 4.06 (s, 3H), 3.80 - 3.67 (m, 2H),2.61 - 2.56 (m, 1H), 2.46 (s, 3H), 2.10 - 1.24 (m, 10H), 1.11 - 1.01 (m,1H), 0.84 - 0.75 (m, 6H); hLPA₁ IC₅₀= 109 nM. Example 1 162

LCMS, [M + H]⁺ = 464.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.5 Hz,1H), 7.48 (d, J = 8.6 Hz, 1H), 4.76 (d, J = 5.7 Hz, 3H), 4.47 (t, J =6.0 Hz, 1H), 4.37 (d, J = 6.4 Hz, 1H), 4.06 (s, 3H), 3.99 (t, J = 6.0Hz, 2H), 2.70 - 2.61 (m, 1H), 2.46 (s, 3H), 2.07 - 1.44 (m, 12H); hLPA₁IC₅₀ = 60 nM. Example 1 163

LCMS, [M + H]⁺ = 490.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.58 (d, J = 8.5 Hz,1H), 7.27 (d, J = 8.7 Hz, 1H), 4.51 (d, J = 5.6 Hz, 3H), 4.29 (t, J =6.4 Hz, 1H), 4.20 (t, J = 6.4 Hz, 1H), 3.81 (s, 3H), 3.59 (sn 2H), 2.20(s, 3H), 1.79 -1.21 (m, 10H), 0.21 - 0.04 (m, 4H). (Proton α to acid notobserved due to water-suppression); hLPA₁ IC₅₀ = 88 nM. Example 1 164

LCMS, [M + H]⁺ = 472.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.68 (d, J = 8.5 Hz,1H), 7.32 (d, J = 8.6 Hz, 1H), 4.59 (d, J= 5.7 Hz, 3H), 3.91 (s, 4H),3.67 (dd, J = 11.6, 8.6 Hz, 1H), 2.55 - 2.46 (m, 1H), 2.31 (s, 3H),1.92 - 1.29 (m, 8H), 0.86 (s, 3H), 0.84 (s, 3H), 0.69 (d, J = 14.2 Hz,1H), 0.29 (dd, J = 8.6, 4.3 Hz, 1H); hLPA₁ IC₅₀= 65 nM. Example 1 165

LCMS, [M + H]⁺ = 460.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (d, J = 8.5 Hz,1H), 7.52 - 7.44 (m, 2H), 4.74 (br s, 3H), 4.65 (s, 1H), 4.04 (s, 3H),2.44 (s, 3H), 2.00 - 1.30 (m, 10H), 1.28 - 1.18 (m, 2H), 1.11 (d, J =6.1 Hz, 3H), 0.84 (t, J= 7.4 Hz, 3H). (Proton α to acid not observed dueto water-suppression); hLPA₁ IC₅₀ = 34 nM. Example 1 166

LCMS, [M + H]⁺ = 514.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (d, J = 8.5 Hz,1H), 7.58 (s, 1H), 7.53 (d, J = 8.6 Hz, 1H), 4.76 (d, J = 5.4 Hz, 2H),4.71 (s, 1H), 4.05 (s, 3H), 3.97 (t, J = 6.5 Hz, 2H), 2.24 (br s, 2H),1.97 - 1.40 (m, 10H). (Proton α to carboxylic acid and —CH₃ on thepyridine are not observed due to water-suppression); hLPA₁ IC₅₀ = 121nM. Example 1 167

LCMS, [M + H]⁺ = 457.9; ¹H NMR (500 MHz, DMSO-d₆) δ 7.63 (d, J = 8.5 Hz,1H), 7.29 (d, J = 8.6 Hz, 1H), 4.58 (s, 1H), 4.54 (s, 2H), 3.95 -3.89(m, 1H), 3.84 (s, 3H), 2.46 - 2.38 (m, 1H), 1.86 -1.23 (m, 8H), 1.01 -0.92 (m, 3H), 0.76 - 0.67 (m, 1H), 0.27 - -0.03 (m, J 4H). (—CH₃ on thepyridine are not observed due to water-suppression); hLPA₁ IC₅₀= 427 nM.Example 1 168

LCMS, [M + H]⁺ = 472.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.5 Hz,1H), 7.49 (d, J = 8.6 Hz, 1H), 7.41 (br s, 1H), 4.88 - 4.79 (m, 1H),4.74 (s, 3H), 4.05 (s, 3H), 2.45 (s, 3H), 2.14 - 1.46 (m, 12H), 1.08 (s,6H). (Proton α to carboxylic acid Example 1 not observed due towater-suppression); hLPA₁ IC₅₀ = 90 nM. 169

LCMS, [M + H]⁺ = 500.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.5 Hz,1H), 7.47 (d, J = 8.6 Hz, 1H), 4.77 (d, J = 5.4 Hz, 3H), 4.06 (s, 3H),4.01 (t, J = 6.4 Hz, 2H), 2.70 - 2.62 (m, 1H), 2.46 (s, 3H), 2.32 - 2.19(m, 2H), 2.07 - 1.47 (m, 10H); hLPA₁ IC₅₀= 55 nM. Example 1 170

LCMS, [M + H]⁺ = 460.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.6 Hz,1H), 7.48 (d, J = 8.6 Hz, 1H), 4.76 (d, J = 11.4 Hz, 3H), 4.48 (s, 1H),4.05 (s, 3H), 2.71 - 2.59 (m, 1H), 2.46 (s, 3H), 2.07 -1.45 (m, 9H),1.11 - 0.95 (m, 3H), 0.80 (br s, 6H); hLPA₁ IC₅₀ = 92 nM. Example 1 171

LCMS, [M + H]⁺ = 460.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.5 Hz,1H), 7.48 (d, J = 8.6 Hz, 1H), 4.75 (d, J = 7.9 Hz, 3H), 4.67 (s, 1H),4.05 (s, 3H), 2.69 - 2.62 (m, 1H), 2.46 (s, 3H), 2.09 -1.20 (m, 12H),1.15 - 1.05 (m, 3H), 0.84 (t, J = 7.8 Hz, 3H); hLPA₁ IC₅₀ = 76 nM.Example 1 172

LCMS, [M + H]⁺ = 446.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.5 Hz,1H), 7.49 (d, J = 8.7 Hz, 1H), 4.78 (s, 1H), 4.75 (s, 2H), 4.62 -4.54(m, 1H), 4.05 (s, 3H), 2.66 - 2.59 (m, 1H), 2.45 (s, 3H), 2.06 - 1.39(m, 10H), 1.11 (d, J = 6.2 Hz, 3H), 0.81 (t, J = 8.4 Hz, 3H); hLPA₁IC₅₀= 152 nM. Example 1 173

LCMS, [M + H]⁺ = 460.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.6 Hz,1H), 7.52 (s, 1H), 7.48 (d, J = 8.7 Hz, 1H), 4.78 (s, 1H), 4.75 (s, 2H),4.51 - 4.43 (m, 1H), 4.04 (s, 3H), 2.66 - 2.59 (m, 1H), 2.45 (s, 3H),2.06 - 1.40 (m, 9H), 1.06 (d, J = 6.4 Hz, 3H), 0.81 (t, J = 6.9 Hz, 6H);hLPA₁ IC₅₀= 167 nM. Example 1 174

LCMS, [M + H]⁺ = 486.2; ¹H NMR (500 MHz, DMSO-d₆) δ 8.11 (s, 1H), 7.82(d, J = 8.6 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 5.33 - 5.18 (m, 1H), 4.80(d, J = 5.1 Hz, 2H), 4.77 (s, 1H), 4.03 (s, 3H), 2.66 -2.57 (m, 1H),2.42 (s, 3H), 2.04 - 1.41 (m, 8H), 1.30 (d, J = 6.6 Hz, 3H); hLPA₁ IC₅₀= 101 nM. Example 1 175

LCMS, [M + H]⁺ = 446.0; ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.6 Hz,1H), 7.48 (d, J = 8.5 Hz, 1H), 4.78 (s, 1H), 4.75 (s, 2H), 4.62 -4.55(m, 1H), 4.05 (s, 3H). 2.67 - 2.58 (m, 1H), 2.45 (s, 3H), 2.05 - 1.39(m, 10H), 1.10 (s, 3H), 0.80 (s, 3H); hLPA₁ IC₅₀= 95 nM. Example 1 176

LCMS, [M + H]⁺ = 458.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.62 (d, J = 8.5 Hz,1H), 7.27 (d, J = 8.6 Hz, 1H), 4.55 (br s, 3H), 3.92 (s, 1H), 3.84 (s,3H), 2.46 - 2.39 (m, 1H), 2.24 (s, 3H), 1.85 - 1.21 (m, 8H), 0.97 (d, J= 6.7 Hz, 3H), 0.72 (br s, 1H), 0.28 - -0.06 (m, 4H); hLPA₁ IC₅₀= 106nM. Example 1 177

LCMS, [M + H]⁺ = 444.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (d, J = 8.6 Hz,1H), 7.52 (s, 1H), 7.47 (d, J = 8.6 Hz, 1H), 4.77 (br s, 2H), 4.71 (brs, 2H), 4.04 (s, 3H), 2.66 - 2.56 (m, 1H), 2.44 (s, 3H), 2.23 - 1.43 (m,14H); hLPA₁ IC₅₀ = 148 nM. Example 1 178

LCMS, [M + H]⁺ = 480.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.5 Hz,1H), 7.80 (s, 1H), 7.49 (d, J = 8.7 Hz, 1H), 4.77 (br s, 4H), 4.04 (s,3H), 3.05 - 2.92 (m, 2H), 2.62 - 2.52 (m, 3H), 2.45 (s, 3H), 2.04 - 1.43(m, 8H); hLPA₁ IC₅₀ = 102 nM. Example 1 179

LCMS, [M + H]⁺ = 458.4; ¹H NMR (500 MHz, DMSO-d₆) δ 7.62 (d, J = 8.5 Hz,1H), 7.34 (s, 1H), 7.28 (d, J = 8.6 Hz, 1H), 4.55 (br s, 3H), 3.85 (s,3H), 3.57 (d, J = 7.3 Hz, 2H), 2.44 - 2.35 (m, 1H), 2.24 (s, 3H), 1.81 -1.25 (m, 8H), 0.75 (d, J = 6.0 Hz, 3H), 0.58 - -0.03 (m, 4H); hLPA₁ IC₅₀= 46 nM. Example 1 180

LCMS, [M + H]⁺ = 480.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.5 Hz,1H), 7.73 (s, 1H), 7.48 (d, J = 8.6 Hz, 1H), 4.79 (br s, 3H), 4.22 -4.14 (m, 1H), 4.06 (s, 3H), 3.87 (t, J = 10.2 Hz, 1H), 2.68 - 2.58 (m,1H), 2.45 (s, 3H), 2.10 - 1.29 (m, 11H); hLPA₁ IC₅₀ = 53 nM. Example 1181

LCMS, [M + H]⁺ = 486.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.8 Hz,1H), 7.73 (s, 1H), 7.49 (d, J = 8.7 Hz, 1H), 4.79 (d, J = 5.2 Hz, 3H),4.19 (s, 2H), 4.05 (s, 3H), 2.67 - 2.58 (m, 3H), 2.45 (s, 3H), 2.06 -1.46 (m, 8H); hLPA₁ IC₅₀ = 96 nM. Example 1 182

LCMS, [M + H]⁺ = 494.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.5 Hz,1H), 7.67 (s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 4.79 (br s, 3H), 4.06 (s,3H), 4.03 (d, J = 6.0 Hz, 2H), 2.69 - 2.59 (m, 3H), 2.46 (s, 3H), 2.43 -2.27 (m, 3H), 2.07 - 1.46 (m, 8H); hLPA₁ IC₅₀ = 85 nM. Example 1 183

LCMS, [M + H]⁺ = 458.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.65 (d, J = 8.5 Hz,1H), 7.28 (d, J = 8.6 Hz, 1H), 4.55 (br s, 3H), 3.87 (s, 3H), 3.60 (d, J= 7.1 Hz, 2H), 2.51 -2.39 (m, 1H), 2.27 (s, 3H), 1.87 - 1.26 (m, 8H),0.77 (d, J = 6.0 Hz, 3H), 0.55 (s, 1H), 0.44 (s, 1H), 0.22 - 0.14 (m,1H), 0.03 (dd, J = 8.7, 4.5 Hz, 1H); hLPA₁ IC₅₀ = 32 nM. Example 1 184

LCMS, [M + H]⁺ = 472.4; ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.6 Hz,1H), 7.54 (s, 1H), 7.49 (d, J = 8.7 Hz, 1H), 4.78 (s, 1H), 4.75 (d, J=5.1 Hz, 2H), 4.06 (s, 3H), 4.01 - 3.95 (m, 1H), 3.84 -3.78 (m, 1H), 2.63(t, J = 11.1 Hz, 1H), 2.45 (s, 3H), 2.06 -1.44 (m, 8H), 0.97 (br s, 1H),0.89 (br s, 3H), 0.50 (br s, 1H), 0.37 - 0.25 (m, 2H), 0.08 (s, 1H),0.01 (s, 1H); hLPA₁ IC₅₀ = 41 nM. Example 1 195

LCMS, [M + H]⁺ = 472.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.67 (d, J= 8.5 Hz,1H), 7.34 (d, J = 8.5 Hz, 2H), 4.66 - 4.53 (m, 3H), 3.94 - 3.84 (m, 5H),1.89 - 1.20 (m, 10H), 0.82 (s, 3H), 0.08 (s, 2H), -0.00 (d, J = 4.4 Hz,2H). (Proton α to carboxylic acid and —CH₃ on pyridine not observed dueto water-suppression); hLPA₁ IC₅₀ = 72 nM. Example 1 196

LCMS, [M + H]⁺ = 496.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (d, J = 8.5 Hz,1H), 7.64 (s, 1H), 7.50 (d, J = 8.6 Hz, 1H), 6.16 (t, J = 56.5 Hz, 1H),4.80 (br s, 3H), 4.06 (s, 3H), 3.91 - 3.81 (m, 2H), 2.64 (t, J = 10.9Hz, 1H), 2.46 (s, 3H), 2.08 - 1.44 (m, 11H), 0.93 (d, J = 6.5 Hz, 3H);hLPA₁ IC₅₀ = 83 nM. Example 1 197

LCMS, [M + H]⁺ = 460.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (d, J = 8.4 Hz,1H), 7.52 (d, J = 8.3 Hz, 2H), 4.74 (br s, 3H), 4.05 (s, 3H), 4.0 -3.94(m, 2H), 2.43 (s, 3H), 1.93 - 1.34 (m, 11H), 0.85 (d, J = 6.6 Hz, 6H).(Proton α to carboxylic acid not observed due to water-suppression);hLPA₁ IC₅₀ = 16 nM. Example 1 198

LCMS, [M + H]⁺ = 522.3; ¹H NMR (500 MHz, DMSO-d₆) δ 8.23 - 8.13 (m, 1H),7.85 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 4.85 (d, J = 5.3 Hz,2H), 4.81 - 4.70 (m, 3H), 4.05 (s,3H), 2.63 (t, J = 11.3 Hz, 1H), 2.07 -1.44 (m, 8H); hLPA₁ IC₅₀ = 45 nM. Example 1 199

LCMS, [M + H]⁺ = 473.9; ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J = 8.4 Hz,1H), 7.49 (d, J = 8.6 Hz, 1H), 7.42 (s, 1H), 4.75 (s, 2H), 4.74 (s, 1H),4.06 (s, 3H), 3.92 (t, J = 6.6 Hz, 2H), 2.66 - 2.58 (m, 1H), 2.46 (s,3H), 2.44 -2.39 (m, 2H), 2.05 (s, 3H), 2.02 -1.48 (m, 10H); hLPA₁ IC₅₀ =312 nM. Example 1 200

LCMS, [M + H]⁺ = 468.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.93 (s, 1H), 7.84(d, J = 8.5 Hz, 1H), 7.48 (d, J= 8.7 Hz, 1H), 4.81 (d, J = 5.3 Hz, 2H),4.78 (br s, 1H), 4.25 (t, J = 13.5 Hz, 2H), 4.05 (s, 3H), 2.67 - 2.59(m, 1H), 2.45 (s, 3H), 2.05 - 1.45 (m, 11H); hLPA₁ IC₅₀ = 82 nM Example1 201

LCMS, [M + H]⁺ = 470.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.58 (d, J = 8.5 Hz,1H), 7.37 (s, 1H), 7.25 (d, J = 8.6 Hz, 1H), 4.75 (br s, 1H), 4.50 (d, J= 14.8 Hz, 3H), 3.80 (s, 3H), 2.20 (s, 3H), 2.03 - 1.18 (m, 12H), 0.23 -0.07 (m, 4H). (Proton α to carboxylic acid not observed due towater-suppression); hLPA₁ IC₅₀ = 42 nM. Example 1 202

LCMS, [M + H]⁺ = 482.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J = 8.6 Hz,1H), 7.63 (s, 1H), 7.48 (d, J = 8.7 Hz, 1H), 4.77 (d, J = 5.4 Hz, 3H),4.11 (t, J = 6.5 Hz, 2H), 4.04 (s, 3H), 2.62 (t, J = 11.0 Hz, 1H), 2.44(s, 3H), 2.24 -1.46 (m, 13H); hLPA₁ IC₅₀ = 86 nM. Example 1 203

LCMS, [M+H]⁺= 460.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J=8.5 Hz, 1H),7.47 (d, J=8.7 Hz, 1H), 5.12 (s, 2H), 4.79 - 4.72 (m, 1H), 4.01 (s, 3H),3.83 (d, J=6.5 Hz, 2H), 2.76 (s, 3H), 2.68 -2.59 (m, 1H), 2.44 (s, 3H),2.04 - 1.47 (m, 9H), 0.87 (d, J=6.6 Hz, 6H); hLPA₁ IC₅₀ = 91 nM. Example2 204

LCMS, [M+H]⁺ = 500.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (br d, J=8.5 Hz,1H), 7.76 (br s, 1H), 7.50 (d, J=8.5 Hz, 1H), 4.88 - 4.69 (m, 3H),4.17 - 4.00 (m, 5H), 2.66 - 2.58 (m, 1H), 2.45 (s, 3H), 2.06 - 1.45 (m,9H), 1.07 (br d, J=7.0 Hz, 3H); hLPA₁ IC₅₀ = 96 nM. Example 1 205

LC-MS, [M+H]⁺ = 458.2; ¹H NMR (500 MHz, DMSO-d₆) 7.87 (d, J=8.5 Hz, 1H),7.50 (d, J=8.8 Hz, 1H), 5.15 (s, 2H), 4.83 - 4.73 (m, 1H), 4.03 (s, 3H),3.89 (br d, J=7.2 Hz, 2H), 2.76 (br s, 3H), 2.70 - 2.58 (m, 1H), 2.45(s, 3H), 2.09 - 1.97 (m, 1H), 1.93 -1.75 (m, 3H), 1.71 - 1.45 (m, 4H),1.18 - 1.01 (m, 1H), 0.57 - 0.43 (m, 2H), 0.32 - 0.19 (m, 2H). 30 of 31protons found; hLPA₁ IC₅₀ = 333 nM. Example 2

Example 206.(1S,3S)-3-((6-(5-(((((4,4-difluoropentyl)oxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylicAcid

206A. Methyl(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((((4-oxopentyl)oxy)carbonyl)amino)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of methyl(1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate(synthesized as for Example 1H, except using (1S, 3R)-methyl 3-hydroxycyclohexanecarboxylate rather than the isopropyl ester; 25 mg, 0.070mmol) and 4-nitrophenyl (4-oxopentyl) carbonate (22 mg, 0.083 mmol) inTHF (0.2 mL) was added iPr₂NEt (0.036 mL, 0.209 mmol). The mixture wasstirred at RT for 52 h, then was concentrated in vacuo. The residue waschromatographed (12 g SiO_(2;) continuous gradient from 0% to 100% EtOAcin hexanes in 19 min, the hold for 5 min) to give the title compound (31mg, 0.064 mmol, 91% yield) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ8.05 (d, J = 8.6 Hz, 1H), 7.27 (s, 1H), 7.07 (br s, 1H), 4.75 (dq, J =5.0, 2.6 Hz, 1H), 4.63 (d, J = 5.4 Hz, 2H), 4.23 (s, 3H), 4.07 (t, J =6.3 Hz, 2H), 3.73 (s, 3H), 2.86 (tt, J = 10.3, 3.9 Hz, 1H), 2.57 (s,3H), 2.50 (t, J = 7.2 Hz, 2H), 2.19 - 1.61 (m, 13H). LCMS, [M+H]⁺ =488.1.

Example 206

To a solution of Example 206A (25 mg, 0.051 mmol) in DCM (0.5 mL) wasadded DAST (0.027 mL, 0.205 mmol) at 0° C. The reaction mixture wasstirred at RT for 2 h, then was quenched with water (0.5 mL) andconcentrated in vacuo. The residue was dissolved in THF (1 mL) and water(0.5 mL) and LiOH.H₂O (22 mg, 0.51 mmol) wa added. The reaction wasstirred at RT overnight, then was adjusted to pH ~ 5 with 1 N aq. HCland extracted with EtOAc (3 x 2 mL). The combined organic extracts weredried (MgSO₄) and concentrated in vacuo. The crude material was purifiedby preparative LC/MS (Column: XBridge C18, 19 x 200 mm, 5-µm particles;Mobile Phase A: 5:95 MeCN:H₂O with 0.1% TFA; Mobile Phase B: 95:5MeCN:H₂O with 0.1% TFA; Gradient: 10-55% B over 19 min, then a 5-minhold at 100% B; Flow: 20 mL/min). Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to affordthe title compound (17.2 mg, 0.027 mmol, 53% yield; LCMS purity = 97%).LCMS [M + H]⁺ = 496.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.96 (s, 1H), 7.50(d, J = 8.4 Hz, 2H), 4.77 (d, J = 5.5 Hz, 3H), 4.07 (s, 3H), 3.99 (t, J= 6.5 Hz, 2H), 2.70 -2.61 (m, 1H), 2.42 (s, 3H), 2.06 - 1.47 (m, 15H).hLPA₁ IC₅₀ = 71 nM.

Example 207.(1S,3S)-3-((6-(5-((((((R)-2,2-difluorocyclopropyl)methoxy)carbonyl)amino) methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylateDiethylammonium Salt (First Eluting Isomer; the Stereochemistry of theCyclopropyl Chiral Center is Arbitrarily Assigned)

Example 208.(1S,3S)-3-((6-(5-((((((S)-2,2-difluorocyclopropyl)methoxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylateDiethylammonium Salt (Second Eluting Isomer; the Stereochemistry of theCyclopropyl Chiral Center is Arbitrarily Assigned)

The individual diastereomers of Example 180 were separated by SFC(Column: Chiralpak AD-H, 21 x 250 mm, 5 µm; Flow Rate: 45 mL/min; OvenTemperature: 40° C.; BPR Setting: 150 bar; UV wavelength: 255 nm; MobilePhase: 90% CO₂/10% MeOH -0.1% DEA (isocratic); Injection: 0.5 mL of ~14mg/mL in MeOH:MeCN) to give two diastereomers. The chiral purity of bothcompounds were determined to be >93% ee under these analyticalconditions: Column: Chiralpak AD-H, 4.6 x 250 mm, 5 µm (analytical);Flow Rate: 2 mL/min; Oven Temperature: 40° C.; BPR setting: 150 bar; UVwavelength: 254 nm; Mobile Phase: 10% MeOH - 0.1% DEA / 85% CO₂(isocratic). Example 207. First eluting enantiomer: LCMS, [M + H]⁺ =480.2. hLPA₁ IC₅₀ = 44 nM. Example 208. Second eluting enantiomer: LCMS,[M + H]⁺ = 480.2. hLPA₁ IC₅₀ = 57 nM.

Example 209.(±)-Cis-3-((6-(5-((((benzyloxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocyclohexanecarboxylicAcid

209A. (±)-Cis-isopropyl1-fluoro-3-((2-methyl-6-(1-methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexanecarboxylate

To a solution of Example 1C (0.193 g, 0.634 mmol)) and Intermediate 1(0.194 g, 0.951 mmol) in toluene (18 mL) was added Ph₃P (0.317 mL, 1.268mmol) and (E)-diazene-1,2-diylbis (piperidin-1-ylmethanone) (0.320 g,1.268 mmol). The reaction was stirred at 50° C. for 5 h, then was cooledto RT and filtered. The filtrate was concentrated in vacuo. The crudeoil was chromatographed (24 g SiO₂; continuous gradient from 0% to 50%EtOAc in hexane over 10 min) to give the title compound (0.06 g, 0.122mmol, 19.29% yield) as a clear oil. ¹H NMR (500 MHz, CDCl₃) δ 7.86 (d,J=8.5 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 5.31 - 5.17 (m, 2H), 5.04 (dt,J=12.4, 6.3 Hz, 1H), 4.72 - 4.66 (m, 1H), 4.64 - 4.57 (m, 1H), 4.07 (s,3H), 3.82 (tt, J=8.5, 2.5 Hz, 1H), 3.49 - 3.42 (m, 1H), 2.42 (s, 4H),2.08 - 1.39 (m, 13H), 1.24 (dd, J=6.2, 2.6 Hz, 6H).

209B. (±)-Cis-isopropyl1-fluoro-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate

A mixture of Example 209A (0.18 g, 0.367 mmol) and p-TsOH (0.021 g,0.110 mmol) in MeOH (10 mL) was stirred at 60° C. for 3 h, then wascooled to RT and NaHCO₃ (0.031 g, 0.367 mmol) was added. The mixture wasstirred at RT for 1 h, then DCM (10 mL) was added. The mixture wasfiltered; the filtrate was concentrated in vacuo. The crude oil waschromatographed (12 g SiO₂; continuous gradient from 0% to 100% EtOAc inhexane over 14 min) to give the title compound (0.133 g, 0.327 mmol, 89%yield) as a clear oil. ¹H NMR (500 MHz, CDCl₃) δ 7.22 - 7.18 (m, 1H),5.03 (spt, J=6.3 Hz, 1H), 4.74 (d, J=1.1 Hz, 2H), 4.65 (quin, J=5.0 Hz,1H), 3.99 (s, 3H), 2.44 (s, 3H), 2.40 - 2.28 (m, 1H), 2.12 - 1.76 (m,6H), 1.52 - 1.41 (m, 1H), 1.23 (dd, J=6.3, 2.8 Hz, 6H); ¹⁹F NMR (471MHz, CDCl₃) δ -153.01 (s, 1F).

209C. (±)-Cis-isopropyl3-((6-(5-((((benzyloxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocyclohexanecarboxylate

A solution of Example 209B (33 mg, 0.081 mmol), benzylN-[(tert-butoxy)carbonyl] carbamate (30.6 mg, 0.122 mmol), n-Bu₃P (0.030mL, 0.122 mmol), and 1,1′-(azodicarbonyl) dipiperidine (31 mg, 0.122mmol) in toluene (2 mL) was stirred at 50° C. for 3 h, then was cooledto RT. TFA (1 mL) was added and the reaction was stirred at RT for 1 h,then was concentrated in vacuo. The crude oil was purified bypreparative HPLC (Sunfire C18 30 x 100 mm column; detection at 220 nm;flow rate = 40 mL/min; continuous gradient from 20% B to 100% B over 10min + 2 min hold time at 100% B, where A = 90:10:0.1 H₂O:MeCN:TFA and B= 90:10:0.1 MeCN:H₂O:TFA) to give the title compound (40 mg, 0.074 mmol,91% yield) as a clear oil. [M + H]⁺ = 540.3.

Example 209

A mixture of Example 209C (40 mg, 0.074 mmol) and 2.0 M aq. LiOH (1.86mL, 3.71 mmol) in THF (3 mL) was stirred at RT for 3 h. The product waspurified by preparative HPLC (Sunfire C18 30 x 100 mm column; detectionat 220 nm; flow rate = 40 mL/min; continuous gradient from 20% B to 100%B over 10 min + 2 min hold time at 100% B, where A = 90:10:0.1H₂O:MeCN:TFA and B = 90:10:0.1 MeCN:H₂O:TFA) to give the title compound(37.1 mg, 0.058 mmol, 79% yield) as a clear oil. [M + H]⁺ = 498.2; ¹HNMR (400 MHz, CDCl₃) δ 8.06 (d, J=8.4 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H),7.39 - 7.28 (m, 5H), 5.10 (s, 2H), 4.93 (br. s., 1H), 4.59 (s, 2H), 4.16(s, 3H), 2.68 (s, 3H), 2.45 - 2.29 (m, 1H), 2.25 - 1.87 (m, 7H), 1.68(br. s., 1H); ¹⁹F NMR (377 MHz, CDCl₃) δ -154.52 (s, 1F). hLPA₁ IC₅₀ =12 nM.

Example 210.(1R,3S)-3-((6-(5-((((benzyloxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocyclohexane-1-carboxylicAcid

Example 211.(1S,3R)-3-((6-(5-((((benzyloxy)carbonyl)amino)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)-1-fluorocyclohexane-1-carboxylicAcid

The absolute stereochemistry of Examples 210 and 211 were notdetermined - the stereochemistry in the structures shown are arbitrarilydrawn. The two individual enantiomers of Example 209 (32 mg, 0.064 mmol)were obtained by chiral SFC separation: Instrument: Berger MGII-SFC,Column: Chiralpak IC, 21 x 250 mm, 5 µm, Mobile Phase: 20%MeOH / 80%CO₂, Flow Conditions: 45 mL/min, 150 Bar, 40° C.; Detector Wavelength:254 nm, Injections: 0.5 mL of 8 mg/mL solution in MeOH:MeCN (1:1).

Example 210 - first eluting enantiomer (8.4 mg, 0.017 mmol, 25.7%yield); [M + H]⁺ = 498.1; ¹H NMR (400 MHz, CDCl₃) δ 8.06 (br. s., 1H),7.32 (br. s., 6H), 5.08 (br. s., 2H), 4.92 - 4.50 (m, 3H), 4.21 (br. s.,2H), 2.52 (br. s., 4H), 2.32 - 1.27 (m, 8H); ¹⁹F NMR (377 MHz, CDCl₃) δ-149.29 (s, 1F); hLPA₁ IC₅₀ = 5 nM.

Example 211 - second eluting enantiomer (11 mg, 0.022 mmol, 33.7 %yield); [M + H]⁺ = 498.1; ¹H NMR (400 MHz, CDCl₃) δ 8.06 (br. s., 1H),7.32 (br. s., 6H), 5.08 (br. s., 2H), 4.92 - 4.50 (m, 3H), 4.21 (br. s.,2H), 2.52 (br. s., 4H), 2.32 - 1.27 (m, 8H); ¹⁹F NMR (377 MHz, CDCl₃) δ-150.17 (s, 1F); hLPA₁ IC₅₀ = 192 nM.

Intermediate 40. 2,5-dibromo-3-fluoro-6-methylpyridine

Intermediate 40A. 3-fluoro-6-methylpyridin-2-amine

To a solution of 2-bromo-3-fluoro-6-methylpyridine (5.0 g, 26.3 mmol) inethylene glycol (50 mL) and aq. 28% NH₄OH (63 mL; 450 mmol) were addedCu₂O (0.19 g, 1.32 mmol), K₂CO₃ (0.73 g, 5.26 mmol), and N1,N1-dimethylethane-1,2-diamine (0.29 mL, 2.63 mmol). The reaction mixturewas purged with N₂, then was heated at 80° C. overnight in a sealedtube, after which it was cooled to RT and extracted with CH₂Cl₂ (3x).The combined organic extracts were dried (Na₂SO₄), and concentrated invacuo. The residue was chromatographed (SiO₂; continuous gradient from0-100% EtOAc in hexanes) to give the title compound (2.81 g, 85% yield).¹H NMR (500 MHz, CDCl₃) δ 7.11 (dd, J=10.6, 8.1 Hz, 1H), 6.47 (dd,J=8.0, 3.0 Hz, 1H), 4.55 (br s, 2H), 2.38 (s, 3H).

Intermediate 40B. 5-bromo-3-fluoro-6-methylpyridin-2-amine

To a 0° C. solution of Intermediate 34A (3.91 g, 31.0 mmol) in CH₃CN(100 mL) was added portionwise NBS (5.52 g, 31.0 mmol) while maintainingthe reaction temperature at ≤5° C. The reaction mixture was stirred atRT for 30 min, then was concentrated in vacuo. The residue waschromatographed (SiO₂; isocratic 30% EtOAc in hexanes) to give the titlecompound (6.14 g, 97% yield). ¹H NMR (500 MHz, CDCl₃) δ 7.37 (d, J=9.6Hz, 1H), 4.59 (br s, 2H), 2.48 (d, J=1.1 Hz, 3H).

Intermediate 40

To a 0° C. solution of aq. 48% HBr (23.7 mL, 210 mmol, 48%) was addedslowly portionwise Intermediate 34B (6.14 g, 29.9 mmol). Br₂ (3.09 mL,59.9 mmol) was added dropwise while maintaining the reaction temperature≤5° C. The reaction mixture was stirred at 0° C. for 30 min, after whicha solution of NaNO₂ (5.17 g, 74.9 mmol) in water (10 mL) was addeddropwise while maintaining the reaction temperature at ≤5° C. Thereaction mixture was stirred for 30 min at 0° C., then was poured intoice water, basified with 50% aq. NaOH and extracted with EtOAc (2x). Thecombined organic extracts were washed with aq. 10% Na₂S₂O₃, brine, dried(Na₂SO₄), and concentrated in vacuo. The residue was chromatographed(SiO₂; continuous gradient from 0-25% EtOAc in hexanes) to give thetitle compound (3.90 g, 48% yield). ¹H NMR (500 MHz, CDCl₃) δ 7.60 (d,J=6.6 Hz, 1H), 2.64 (d, J=1.4 Hz, 3H).

Intermediate 41. Isopropyl(1S,3S)-3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-5-fluoro-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

Intermediate 41 was prepared using the same synthetic sequence that wasused to prepare Example 1E except that Intermediate 40 was used insteadof the 2,5-dibromo-6-methyl-pyridine that was used for the synthesis ofExample 1A. LCMS, [M+H]⁺ = 407. ¹H NMR (400 MHz, CDCl₃) δ 7.16 (d,J=11.9 Hz, 1H), 5.05 (quin, J=12.5 Hz, 1H), 4.76 (s, 2H), 4.66 (m, 1H),4.13 (s, 3H), 2.77 (m, 1H), 2.50 (d, J=1.1 Hz, 3H), 2.07 - 2.02 (m, 2H),1.97 - 1.86 (m, 2H), 1.81 - 1.62 (m, 4H), 1.27 (dd, J=6.2, 3.7 Hz, 6H).

Intermediate 42.4-(3-fluoro-5-(((1S,3S)-3-(isopropoxycarbonyl)cyclohexyl)oxy)-6-methylpyridin-2-yl)-1-methyl-1H-1,2,3-triazole-5-carboxylicAcid

Intermediate 42 was prepared using the same synthetic sequence that wasused to prepare Example 64B. Intermediate 40 was used instead of2,5-dibromo-6-methylpyridine in the synthetic sequence.

The examples in the following table were synthesized using the generalprocedures described for the preparation of Examples 1 and 64 and usingintermediates 41 and 42; or Example 137.

Ex # Structure & Name Analytical &Biology Data Method 212

LCMS, [M+H]⁺ = 476; ¹H NMR (500 MHz, ¹H NMR (500 MHz, DMSO-d₆) δ 7.56(d, J=11.9 Hz, 1H), 7.49 (br s, 1H), 4.80 (br s, 1H), 4.58 (br d, J=5.2Hz, 2H), 4.07 (s, 3H), 3.92 - 3.87 (m, 2H), 2.64 -2.58 (m, 1H), 2.40 (s,3H), 2.00 - 1.75 (m, 8H), 1.71 -1.62 (m, 3H), 1.59 - 1.50 (m, 2H); hLPA₁IC50 = 112 nM. Example 1 with Intermediate 35 213

LCMS, [M+H]⁺ = 464; ¹H NMR (500 MHz, DMSO-d₆) δ 7.52 (d, J=11.9 Hz, 1H),7.46 (br s, 1H), 4.80 (br s, 1H), 4.56 (br d, J=3.4 Hz, 2H), 4.06 (s,3H), 2.63 (m, 1H), 2.39 (s, 3H), 2.01 (m, 1H), 1.91 - 1.71 (m, 4H),1.67 - 1.46 (m, 4H), 0.81 (br d, J=5.2 Hz, 6H); hLPA₁ IC50 = 382 nM.Example 1 with intermediate 35 214

LCMS, [M+H]⁺ = 488; ¹H NMR (500 MHz, DMSO-d₆) δ 7.52 (br d, J=10.4 Hz,1H), 4.94 (m, 1H), 4.80 (br s, 1H), 4.55 (br s, 2H), 4.06 (s, 3H), 2.63(m, 1H), 2.39 (s, 3H), 2.27 - 2.12 (m, 4H), 2.01 (m, 1H), 1.88 - 1.75(m, 3H), 1.66 - 1.46 (m, 4H), 0.46 -0.31 (m, 4H); hLPA₁ IC50 = 129 nM.Example 1 with intermediate 35 215

LCMS, [M+H]⁺ = 476; ¹H NMR (500 MHz, ¹H NMR (500 MHz, DMSO-d₆) δ 7.50(br d, J=11.6 Hz, 1H), 4.79 (br s, 1H), 4.56 (br s, 2H), 4.06 (s, 3H),3.73 - 3.63 (m, 1H), 2.62 (m, 1H), 2.38 (s, 3H), 2.04 -1.97 (m, 1H),1.89 - 1.75 (m, 3H), 1.66 - 1.46 (m, 5H), 0.99 (br s, 3H), 0.37 (br s,2H), 0.25 (br s, 2H); hLPA₁ IC₅₀ = 112 nM. Example 1 with intermediate35 216

LCMS, [M+H]⁺ = 490; ¹H NMR (500 MHz, ¹H NMR (500 MHz, DMSO-d₆) δ 7.53(br d, J=12.2 Hz, 1H), 4.79 (br s, 1H), 4.57 (br s, 2H), 4.06 (s, 3H),3.76 (br s, 1H), 2.59 (m, 1H), 2.38 (s, 3H), 1.99 - 1.92 (m, 1H), 1.89 -1.79 (m, 4H), 1.68 - 1.47 (m, 4H), 1.29 -1.21 (m, 2H), 0.85 - 0.78 (m,3H), 0.35 (br s, 2H), 0.26 (br s, 2H); hLPA₁ IC₅₀ = 46 nM. Example 1with intermediate 35 217

LCMS, (M+H)⁺ = 450; ¹H NMR (500 MHz, DMSO-d₆) δ 7.95 (s, 1H), 7.50 (brd, J=11.9 Hz, 1H), 4.80 (br s, 1H), 3.88 (s, 3H), 3.47 - 3.30 ( br m,2H), 2.61 (m, 1H), 2.36 (s, 3H), 2.04 - 1.96 (m, 1H), 1.89 - 1.74 (m,3H), 1.66 -1.47 (m, 5H), 1.40 - 1.18 (br m, 2H), 0.84 (br s, 3H); hLPA₁IC₅₀ = 72 nM. Example 64 & Scheme 7 using Intermediate 36 218

LCMS, (M+H)⁺ = 448.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.94 (s, 1H), 7.49 (brd, J=12.2 Hz, 1H), 4.80 (br s, 1H), 3.89 (s, 3H), 2.61 (m, 1H), 2.36 (s,3H), 2.03 - 1.96 (m, 1H), 1.89 - 1.73 (m, 3H), 1.65 - 1.45 (m, 4H), 1.17-0.94 (m, 1H), 0.47 (br s, 2H), 0.22 (br s, 2H); hLPA₁ IC₅₀ = 300 nM.Example 64 & Scheme 7 using Intermediate 36 219

LCMS, (M+H)⁺ = 450; ¹H NMR (500 MHz, DMSO-d₆) δ 7.95 (s, 1H), 7.50 (brd, J=12.2 Hz, 1H), 4.81 (br s, 1H), 3.89 (s, 3H), 3.34 (m, 1H), 2.61 (m,1H), 2.36 (s, 3H), 2.01 (m, 1H), 1.90 - 1.75 (m, 3H), 1.67 - 1.45 (m,4H), 0.86 (m, 6H); hLPA₁ IC₅₀ = 152 nM. Example 64 & Scheme 7 usingIntermediate 36 220

LCMS, [M + H]⁺ = 404.3; ¹H NMR (DMSO-d₆) δ: 8.26 (d, J=2.4 Hz, 1H), 7.85(d, J=8.9 Hz, 1H), 7.51 (dd, J=8.7, 2.6 Hz, 1H), 4.74 (br s, 2H), 3.85(s, 2H), 3.65-3.76 (m, 1H), 2.61 (br s, 1H), 1.70-1.97 (m, 4H),1.45-1.70 (m, 4H), 1.17 (br s, 6H); hLPA₁ IC₅₀= 389 nM. Example 64 &Scheme 7 221

LCMS, [M + H]⁺ = 404.1; ¹H NMR (400 MHz, CDCl₃) δ 8.72 (d, J=2.9 Hz,1H), 8.38 (d, J=9.0 Hz, 1H), 7.95 (dd, J=9.1, 2.8 Hz, 1H), 5.56 - 5.44(m, 1H), 4.84 (br s, 1H), 4.12 (t, J=6.7 Hz, 2H), 4.08 (s, 3H), 3.00 -2.91 (m, 1H), 2.34 -2.21 (m, 1H), 1.99 - 1.83 (m, 6H), 1.74 - 1.65 (m,3H), 0.97 (t, J=7.5 Hz, 3H); hLPA₁ IC₅₀ = 42 nM. Example 64 & Scheme 7222

LCMS, [M - H]⁺ = 432.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.83 - 7.67 (m, 1H),7.50 - 7.38 (m, 1H), 4.87 - 4.68 (m, 1H), 4.11 - 3.96 (m, 1H), 3.95 -3.81 (m, 3H), 2.72 - 2.62 (m, 1H), 2.57 - 2.54 (m, 3H), 2.46 - 2.33 (m,3H), 2.14 - 1.97 (m, 1H), 1.92 - 1.73 (m, 3H), 1.69 Example 64 & Scheme7

- 1.11 (m, 7H), 0.95 - 0.66 (m, 3H); hLPA₁ IC₅₀ = 21 nM. 223

LCMS, [M - H]⁺ = 444.0; ¹H NMR (500 MHz, DMSO-d₆) δ 7.57 - 7.44 (m, 1H),7.31 - 7.16 (m, 1H), 4.73 - 4.42 (m, 1H), 3.69 - 3.54 (m, 3H), 2.45 -2.34 (m, 1H), 2.28 - 2.23 (m, 6H), 2.18 - 2.06 (m, 3H), 1.91 - 1.48 (m,4H), 1.44 - 1.12 (m, 4H), 0.93 - 0.24 (m, 5H); hLPA₁ IC₅₀ = 52 nM.Example 64 & Scheme 7 224

LCMS, [M - H]⁺ = 444.0; ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 - 7.62 (m, 1H),7.50 - 7.35 (m, 1H), 4.88 - 4.66 (m, 1H), 4.02 - 3.85 (m, 3H), 3.04 -2.82 (m, 1H), 2.68 - 2.61 (m, 1H), 2.43 - 2.27 (m, 3H), 2.10 - 1.96 (m,1H), 1.92 - 1.71 (m, 1.66 1.44 1.21 3H), - (m, 4H), - 0.86 (m, 5H),0.61 - 0.01 (m, 4H); hLPA₁ IC₅₀ = 60 nM Example 64 & Scheme 7 225

LCMS, [M - H]⁺ = 456.0; ¹H NMR (500 MHz, DMSO-d₆) δ 7.78 - 7.62 (m, 1H),7.51 - 7.35 (m, 1H), 5.17 - 4.91 (m, 1H), 4.82 - 4.67 (m, 1H), 3.99 -3.76 (m, 3H), 2.55 (s, 4H), 2.41 - 2.12 (m, 5H), 2.04 -1.91 (m, 1H),1.85 - 1.70 (m, 3H), 1.68 - 1.38 (m, 4H), 0.56 - 0.19 (m, 4H); hLPA₁IC₅₀ = 181 nM. Example 64 & Scheme 7 226

LCMS, [M + H]⁺ =507.2; ¹H NMR (500 MHz, CDCl₃) δ 8.05 (br d, J=8.8 Hz,1H), 7.85 (br d, J=9.1 Hz, 1H), 4.85 (br s, 1H), 4.50 (s, 2H), 4.17 (s,3H), 3.08 - 2.85 (m, 3H), 2.74 (s, 3H), 2.25 - 1.35 (m, 16H), 1.26 -1.07 (m, 2H); hLPA₁ IC₅₀ = 1105 nM. Example 137 227

LCMS, [M + H]⁺ = 515.0; ¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, J=8.8 Hz,1H), 7.80 (d, J=9.0 Hz, 1H), 7.36 - 7.27 (m, 5H), 4.82 (br s, 1H), 4.34(s, 2H), 4.21 (s, 2H), 4.02 (s, 3H), 2.94 - 2.83 (m, 1H), 2.70 (s, 3H),2.19 - 1.61 (m, 8H); hLPA₁ IC₅₀ = 1802 nM. Example 137 228

LCMS, [M + H]⁺ = 543.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (br d, J=8.5Hz, 1H), 7.48 (br d, J=8.5 Hz, 1H), 7.41 - 7.28 (m, 5H), 5.06 (s, 2H),4.77 (br s, 1H), 4.36 (s, 2H), 4.08 (s, 3H), 2.71 (s, 3H), 2.64 (s, 4H),2.43 (s, 3H), 2.01 (br d, J=13.7 Hz, 1H), 1.91 - 1.73 (m, 3H), 1.68 -1.45 (m, 4H); hLPA₁ IC₅₀ = 218 nM. Example 137 229

LCMS, [M + H]⁺ = 509.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (br d, J=8.5Hz, 1H), 7.48 (br d, J=8.9 Hz, 1H), 4.98 (s, 2H), 4.77 (br s, 1H), 4.05(s, 3H), 3.13 (br t, J=7.3 Hz, 2H), 2.78 (s, 3H), 2.69 - 2.59 (m, 1H),2.57 (s, 3H), 2.44 (s, 3H), 2.01 (br d, J=12.5 Hz, 1H), 1.89 - 1.73 (m,3H), 1.68 - 1.44 (m, 6H), 1.31 - 1.21 (m, 2H), 0.88 (t, J=7.3 Hz, 3H)hLPA₁ IC₅₀ = 110 nM Example 137 230

LCMS, (M+H)⁺ = 446.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.73 (br d, J=8.5 Hz,1H), 7.43 (d, J=8.6 Hz, 1H), 4.74 (br s, 1H), 3.91 - 3.85 (m, 3H),3.84 - 3.76 (m, 1H), 2.82 -2.72 (m, 2H), 2.61 (br t, J=10.5 Hz, 1H),2.07 - 1.92 (m, 1H), 1.90 - 1.71 (m, 4H), 1.66 - 1.45 (m, 5H), 1.22 (brt, J=7.4 Hz, 3H), 0.81 (br s, 6H); hLPA₁ IC₅₀ = 17 nM. Example 64 231

LCMS, (M+H)⁺ = 444.4; ¹H NMR (500 MHz, DMSO-d₆) δ 7.73 (d, J=8.5 Hz,1H), 7.46 (br d, J=8.5 Hz, 1H), 4.75 (br s, 1H), 3.94 - 3.79 (m, 4H),2.80 - 2.76 (m, 2H), 2.60 -2.52 (m, 2H), 1.96 (br d, J=13.1 Hz, 1H),1.79 (br s, 4H), 1.66 - 1.46 (m, 5H), 1.23 (br t, J=7.5 Hz, 3H), 0.48(br s, 2H), 0.23 (br s, 1H); hLPA₁ IC₅₀ = 28 nM. Example 64 232

LCMS, (M+H)⁺ = 446.3; ¹H NMR (500 MHz, DMSO-d₆) δ 7.74 (d, J=8.5 Hz,1H), 7.45 (d, J=8.5 Hz, 1H), 4.77 (br s, 1H), 3.89 - 3.85 (m, 3H), 2.78(q, J=7.6 Hz, 2H), 2.60 (br t, J=10.5 Hz, 1H), 2.01 (br d, J=13.7 Hz,1H), 1.85 (br d, J=11.9 Hz, 2H), 1.82 - 1.71 (m, 2H), 1.64 - 1.45 (m,7H), 1.23 (t, J=7.5 Hz, 5H), 0.85 (br s, 3H); hLPA₁ IC₅₀ = 12 nM.Example 64 233

LCMS, (M+H)⁺ = 432.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.72 (d, J=8.5 Hz,1H), 7.46 (d, J=8.5 Hz, 1H), 4.72 (br s, 1H), 4.02 - 3.95 (m, 1H),3.93 - 3.83 (m, 3H), 2.78 (q, J=7.5 Hz, 2H), 2.48 - 2.41 (m, 1H), 1.87(br s, 2H), 1.74 (br d, J=10.5 Hz, 2H), 1.67 - 1.47 (m, 6H), 1.23 (t,J=7.5 Hz, 4H), 0.83 (br s, 3H); hLPA₁ IC₅₀ = 1044 nM. Example 64

Example 234.(1S,3S)-3-((2-methyl-6-(1-methyl-5-((2-methyl-2-phenoxypropanamido)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylicAcid

To a solution of 2-methyl-2-phenoxypropanoic acid (4.2 mg, 0.023 mmol)in DCM (0.3 mL) was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (3µL, 0.023 mmol). The mixture was stirred at RT for 10 min, then wasconcentrated in vacuo. To the residue was added THF (0.3 mL), Example 1H(6 mg, 0.015 mmol) and iPr₂NEt (5 µL, 0.03 mmol). The reaction wasstirred at RT for 1 h, after which MeOH (0.2 mL), THF/water (0.5 mLeach) and LiOH.H₂O (4 mg, 0.1 mmol) were added. The reaction mixture wasstirred at RT overnight; the pH was adjusted to ~ 5 with 1 N aq. HCl.The mixture was extracted with EtOAc (3 x 2 mL). The combined organicfractions were dried (MgSO₄) and concentrated in vacuo. The crudeproduct was purified by preparative LC/MS (Column: XBridge C18, 19 x 200mm, 5-µm particles; Mobile Phase A: 5:95 MeCN:H₂O with 0.1% TFA; MobilePhase B: 95:5 MeCN:H₂O with 0.1% TFA; Gradient: 21-61% B over 20 min,then a 4-min hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and dried via centrifugal evaporation.

The material was further purified using preparative LC/MS (Column:XBridge C18, 19 x 200 mm, 5-µm particles; Mobile Phase A: 5:95 MeCN:H₂Owith 10-mM aq. NH₄OAc; Mobile Phase B: 95:5 MeCN:H₂O with 10-mM aq.NH₄OAc; Gradient: 16-56% B over 25 min, then a 5-min hold at 100% B;Flow: 20 mL/min). Fractions containing the desired product were combinedand dried via centrifugal evaporation to give the title compound (3.9mg; 47% yield; purity by LCMS = 95%). LCMS, [M + H]⁺ = 508.2; ¹H NMR(500 MHz, DMSO-d₆) δ 8.64 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.43 (d, J= 8.6 Hz, 1H), 7.02 (t, J = 7.8 Hz, 2H), 6.86 (t, J = 7.3 Hz, 1H), 6.60(d, J = 8.0 Hz, 2H), 4.73 - 4.66 (m, 3H), 4.10 (s, 3H), 2.49 - 2.43 (m,1H), 2.31 (s, 3H), 1.91 - 1.46 (m, 8H), 1.36 (s, 3H), 1.35 (s, 3H).hLPA₁ IC₅₀= 392 nM.

Example 235.(1S,3S)-3-((6-(5-((2-cyclopentylacetamido)methyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylicAcid

235A. (1S,3S)-ethyl3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexanecarboxylate

To a RT solution of (1S,3S)-ethyl3-((6-(5-(aminomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methyl-pyridin-3-yl)oxy)cyclohexanecarboxylate (20 mg, 0.054 mmol; prepared in the same way as Intermediate1H) and Et₃N (7.5 µL, 0.054 mmol) in DCM (3 mL) under N₂ was added2-cyclopentylacetyl chloride (9.4 mg, 0.064 mmol). The reaction wasstirred at RT for 2 h, then was concentrated in vacuo. The crude titlecompound was used in the next reaction without further purification.

Example 235

To a solution of 235A (20 mg, 0.041 mmol) in THF/MeOH (1.5 mL each) wasadded LiOH.H₂O (3 mg, 0.124 mmol) in water (1.5 mL). The reaction wasstirred for 14 h at RT, then was diluted with water (20 mL), washed withEt₂O (10 mL) and neutralized with 1.5 N aq. HCl (1.5 mL). The mixturewas stirred with 5% MeOH in CHCl₃ (20 mL) for 2 min. The organic phasewas washed with brine, dried (Na₂SO₄) and concentrated in vacuo. Thecrude product was purified by preparative HPLC (Column: Ascentis ExpressC18 (50 x 2.1 mm), 2.7 µm; Mobile Phase A: 5:95 MeCN:water with 10 mMaq. NH4OAc; Mobile Phase B: 95:5 MeCN:water with 10 mM aq. NH4OAc;Temperature: 50° C.; Gradient:0-100% B over 3 min; Flow: 1.1 mL/min) togive the title compound (8.7 mg, 0.019 mmol, 46.2% yield) as a clearoil. [M + H]⁺ = 456.2; ¹H NMR (400 MHz, CD₃OD): δ 7.84 (d, J = 8.40 Hz,1H), 7.47 (d, J = 8.80 Hz, 1H), 4.89 (s, 2H), 4.74-4.78 (m, 1H), 4.16(s, 3H), 2.71-2.79 (m, 1H), 2.56 (s, 3H), 2.10-2.21 (m, 3H), 1.91-1.97(m, 3H), 1.49-1.78 (m, 11H), 1.07-1.12 (m, 2H); hLPA₁ IC₅₀ = 105 nM

The examples in the following table were synthesized according to theprocedures described for the synthesis of Example 235.

Ex # Structure & Name Analytical & Biological Data 236

LCMS, [M + H]⁺ = 442.2; ¹H NMR (400 MHz, CD₃OD): δ 8.42 (s, 1H), 8.00(d, J = 9.20 Hz, 1H), 7.53 (dd, J = 2.40, 8.80 Hz, 1H), 4.74-4.79 (m,1H), 4.52 (s, 2H), 4.20 (s, 3H), 2.78-2.84 (m, 1H), 2.06-2.20 (m, 3H),1.90-2.02 (m, 3H), 1.49-1.84 (m, 11H), 1.03-1.10 (m, 2H); hLPA₁ IC₅₀ =569 nM. 237

LCMS, [M + H]⁺ = 430.2; ¹H NMR (400 MHz, CD₃OD): δ 7.84 (d, J = 8.40 Hz,1H), 7.47 (d, J = 8.80 Hz, 1H), 4.89 (s, 2H), 4.74-4.78 (m, 1H), 4.16(s, 3H), 2.71-2.79 (m, 1H), 2.56 (s, 3H), 2.21 (t, J = 7.60 Hz, 2H),2.09-2.12 (m, 1H), 1.92-1.98 (m, 3H), 1.61-1.78 (m, 4H), 1.55 (p, 2H),1.25-1.28 (m, 2H), 0.87 (t, J = 7.20 Hz, 3H); hLPA₁ IC₅₀ = 783 nM.

Example 238.(1S,3S)-3-((2-methyl-6-(1-methyl-5-(2-(2-phenylacetamido)ethyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylicAcid

238A. Methyl(1S,3S)-3-((6-(5-(hydroxymethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

The title compound was synthesized using the same procedures as for thepreparation of Intermediate 1E, except that (1S, 3R)-methyl3-hydroxycyclohexane carboxylate was used. ¹H NMR (400 MHz, CDCl₃) δ8.09 (d, J = 8.7 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 4.81 (s, 2H), 4.72(dp, J = 5.1, 2.7 Hz, 1H), 4.07 (s, 3H), 3.69 (s, 3H), 2.82 (tt, J =10.2, 3.9 Hz, 1H), 2.53 (s, 3H), 2.19 - 1.54 (m, 8H). LC-MS, [M+H]⁺ =361.2.

238B. Methyl(1S,3S)-3-((6-(5-(bromomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a 0° C. solution of 238A (1.0 g, 2.77 mmol) in DCM (25 mL) was addedPBr₃ (0.26 mL, 2.8 mmol). The reaction mixture was stirred at 0° C. for1 h, then was neutralized by slow addition of satd aq. NaHCO₃; themixture was extracted with EtOAc (3 x 25 mL). The combined organicextracts were washed with water and brine (15 mL each), dried (MgSO₄)and concentrated in vacuo. The crude product was chromatographed (SiO₂;continuous gradient from 0% to 100% EtOAc in hexanes over 20 min) togive the title compound as a white foam (1.10 g, 2.6 mmol, 92% yield),MS (ESI) m/z: 425.1 (M+2+H)⁺.

238C. Methyl(1S,3S)-3-((6-(5-(cyanomethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a solution of 238B (1.10 g, 2.60 mmol) in MeCN (10 mL) was added NaCN(0.127 g, 2.60 mmol) in DMSO (10 mL) portionwise. The reaction mixturewas stirred at 0° C. for 30 min, then was partitioned between EtOAc andwater. The aqueous phase was extracted with EtOAc (3 X 20 mL). Thecombined organic extracts were concentrated in vacuo. The crude productwas chromatographed (SiO₂; continuous gradient from 0% to 100% EtOAc inhexanes over 20 min) to give the title compound as white solid (0.864 g,2.34 mmol, 90% yield). MS(+) MS = 370.2 ¹H NMR (400 MHz, CDCl₃) δ 8.28 -7.77 (m, 1H), 7.23 (d, J=8.8 Hz, 1H), 4.79 - 4.55 (m, 3H), 4.20 (s, 3H),3.72 (s, 3H), 3.06 -2.72 (m, 1H), 2.53 (s, 3H), 2.25 - 2.08 (m, 1H),2.03 - 1.59 (m, 7H)

238D. Methyl(1S,3S)-3-((6-(5-(2-aminoethyl)-1-methyl-1H-1,2,3-triazol-4-yl)-2-methylpyridin-3-yl)oxy)cyclohexane-1-carboxylate

To a 0° C. solution of 238C (155 mg, 0.42 mmol) in MeOH (5 mL) was addedNiCl₂.6H₂O (10 mg, 0.042 mmol) and NaBH₄ (32 mg, 0.84 mmol). Thereaction mixture was stirred at 0° C. for 1 h; water was added and themixture was extracted with EtOAc (3 X 10 mL). The combined organicextracts were dried (Na₂SO₄) and concentrated in vacuo. The crudeproduct was purified by preparative LC/MS: Column: Waters XBridge C18,19 x 200 mm, 5-µm particles; Guard Column: Waters XBridge C18, 19 x 10mm, 5-µm particles; Mobile Phase A: 5:95 MeCN:H₂O with 0.1% TFA; MobilePhase B: 95:5 MeCN:H₂O with 0.1% TFA; Gradient: 50-90% B over 20 min,then a 5-min hold at 100% B; Flow: 20 mL/min. Fractions containing thedesired product were combined and concentrated in vacuo by centrifugalevaporation to give the title compound. (130 mg; 0.35 mmol, 83% yield)¹H NMR (400 MHz, CDCl₃) δ 8.99 (br s, 1H), 8.63 (br s, 1H), 7.83 -7.70(m, 1H), 7.62 (d, J=9.0 Hz, 1H), 4.79 (br s, 1H), 4.08 (s, 3H), 3.72 (s,3H), 3.37 (br d, J=5.1 Hz, 4H), 2.84 (br d, J=4.6 Hz, 1H), 2.56 (s, 3H),2.16 - 2.02 (m, 2H), 2.00 - 1.84 (m, 2H), 1.82 - 1.56 (m, 4H)

Example 238

To a solution of 238D (8 mg, 0.021 mmol) in THF/satd aq. NaHCO₃ (1 mLeach) was added 2-phenylacetyl chloride (3.3 mg, 0.021 mmol). Thereaction mixture was stirred at RT for 1h, then EtOAc (2 mL) was added.The aqueous layer was extracted with EtOAc (2 × 1 mL). The combinedorganic layers were washed with brine, dried (MgSO₄) and concentrated invacuo to give the crude 2-phenyl acetamide ester (LCMS [M + H]⁺ =492.3), which was used in the next step without further purification.The crude product was dissolved in THF (1 mL) and 2 M aq. LiOH (60 µL,0.12 mmol) was added. The reaction mixute was stirred at RT for 18 h,then was concentrated in vacuo. The residue was dissolved in H₂O (1 mL);the pH was adjusted with 1N aq. HCl to ~3 and the mixture was extractedwith EtOAc (2 × 1 mL). The combined organic extracts were washed withbrine (1 mL), dried (MgSO₄) and concentrated in vacuo. The crude productwas purified by preparative LC/MS: Column: Waters XBridge C18, 19 x 200mm, 5-µm particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-µmparticles; Mobile Phase A: 5:95 MeCN:H₂O with 0.1% TFA; Mobile Phase B:95:5 MeCN:H₂O with 0.1% TFA; Gradient: 50-90% B over 20 min, then a5-min hold at 100% B; Flow: 20 mL/min. Fractions containing the desiredproduct were combined and concentrated in vacuo by centrifugalevaporation to give the title compound as a colorless oil. (6.9 mg,0.012 mmol, 54.1% yield). LCMS, [M + H]⁺ = 478.1; ¹H NMR (DMSO-d₆) δ:8.10 (br s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.46 (br d, J=8.6 Hz, 1H),7.22-7.29 (m, 2H), 7.13-7.22 (m, 3H), 4.74 (br s, 1H), 3.89 (s, 3H),3.21-3.65 (m, 2H), 2.60 (br s, 1H), 2.55 (s, 3H), 2.44 (s, 3H), 1.97 (brd, J=13.5 Hz, 1H), 1.75-1.92 (m, 4H), 1.60-1.71 (m, 2H), 1.49-1.60 (m,2H); hLPA₁ IC₅₀= 138 nM.

The examples in the following table were synthesized according to theprocedures described for the preparation of Example 238.

Ex # Structure & Name Analytical & Biological Data 239

LCMS [M + H]⁺ = 500.1; ¹H NMR (DMSO-d₆) δ: 7.91 (br s, 1H), 7.82 (d,J=8.6 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 4.75 (br s, 1H), 4.00 (s, 3H),3.25-3.59 (m, 2H), 2.61-3.01 (m, 2H), 2.55 (s, 4H), 2.47 (s, 2H),1.92-2.08 (m, 2H), 1.76-1.91 (m, 5H), 1.47-1.71 (m, 4H), 1.11-1.22 (m,1H), 0.98 (dd, J=14.0, 6.4 Hz, 1H), 0.84 (s, 8H), 0.81 (br d, J=6.4 Hz,2H); hLPA₁ IC₅₀ = 1021 nM. 240

LCMS, [M + H]⁺ = 458.1; ¹H NMR (DMSO-d₆) δ: 8.02 (br t, J=5.3 Hz, 1H),7.82 (d, J=8.5 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 4.65-4.92 (m, 1H), 3.99(s, 3H), 3.37 (br s, 1H), 3.21-3.30 (m, 1H), 2.60-2.68 (m, 1H),2.55-2.59 (m, 1H), 2.45 (s, 3H), 2.02 (br d, J=14.0 Hz, 1H), 1.90-1.97(m, 2H), 1.87 (br d, J=13.4 Hz, 1H), 1.75-1.83 (m, 2H), 1.60-1.67 (m,2H), 1.46-1.59 (m, 2H), 1.34-1.42 (m, 1H), 1.23-1.30 (m, 2H), 1.17 (t,J=7.3 Hz, 1H), 0.78 (d, J=6.7 Hz, 6H); hLPA₁ IC₅₀ = 1012 nM.

Other features of the invention should become apparent in the course ofthe above descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof. The present invention may be embodied in other specific formswithout departing from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsounderstood that each individual element of the embodiments is its ownindependent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

What is claimed is:
 1. A compound of Formula (IIc):

or a stereoisomer, tautomer, or pharmaceutically acceptable salt orsolvate thereof, wherein: X¹, X², X³, and X⁴ are each independently CR⁶or N; provided that no more than two of X¹, X², X³, or X⁴ are N; R¹ is(—CH₂)_(a)R⁹; a is an integer of 0 or 1; R² is each independently halo,cyano, hydroxyl, amino, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₄₋₆ heterocyclyl,alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl,haloalkoxyalkyl, or haloalkoxy; R³ and R^(4a) are each independentlyhydrogen or C₁₋₄ alkyl; R⁴ is C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, 6 to10-membered aryl, -(C₁₋₆ alkylene)-(C₃₋₈ cycloalkyl), or -(C₁₋₆alkylene)-(6 to 10-membered aryl); wherein each of the alkyl, alkenyl,cycloalkyl, aryl, heterocyclyl, and heteroaryl, by itself or as part ofother moiety, is independently substituted with 0 to 3 R⁸; oralternatively, R³ and R⁴, taken together with the N and O to which theyare attached, form a 4- to 6-membered heterocyclic ring moiety which issubstituted with 0 to 3 R⁸; R⁵ is hydrogen, C₁₋₆ alkyl, alkylamino,haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl,alkoxy, or haloalkoxy; R⁶ is hydrogen, halo, cyano, hydroxyl, amino,C₁₋₆ alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl,alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R^(7a) isindependently hydrogen, halo, oxo, cyano, hydroxyl, amino, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, C₄₋₆ heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl,aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R⁸ iseach independently deuterium, halo, hydroxyl, amino, cyano, C₁₋₆ alkyl,C₁₋₆ deuterated alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, alkylamino,haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl,alkoxy, haloalkoxy, -CHO, phenyl, or 5 to 6 membered heteroaryl; oralternatively, two R⁸, taken together with the atoms to which they areattached, form a 3 to 6-membered carbocyclic ring or a 3 to 6-memberedheterocyclic ring each of which is independently substituted with 0 to 3R¹²; R⁹ is selected from —CN, —C(O)OR¹⁰, —C(O)NR^(11a)R^(11b),

R^(e) is C₁₋₆ alkyl, C₃₋₆ cycloalkyl, haloalkyl, hydroxyalkyl,aminoalkyl, alkoxyalkyl, or haloalkoxyalkyl; R¹⁰ is hydrogen or C₁₋₁₀alkyl; R^(11a) and R^(11b) are each independently hydrogen, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, C₄₋₆ heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl,aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R¹² ishalo, cyano, hydroxyl, amino, C₁₋₆ alkyl, alkylamino, haloalkyl,hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy,haloalkoxy, phenyl, or 5 to 6 membered heteroaryl; f is an integer of 0,1, or 2; and n is 0 or
 1. 2. The compound according to claim 1, whereinR¹ is CO₂H.
 3. The compound according to claim 1, wherein R⁴ is C₁₋₁₀alkyl, C₁₋₁₀ haloalkyl, C₃₋₆ cycloalkyl, -(C₁₋₄ alkylene)-(C₃₋₆cycloalkyl), (C₁₋₄ alkylene)-(C₁₋₆ alkoxy), or -(C₁₋₄ alkylene)-phenyl;wherein each of the alkyl, alkylene, cycloalkyl, and phenyl, by itselfor as part of another group, is independently substituted with 0 to 3R⁸; and R⁸ is each independently halo, hydroxyl, amino, cyano, C₁₋₆alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,haloalkoxyalkyl, alkoxy, or haloalkoxy; or alternatively, two R⁸, takentogether with the atom(s) to which they are attached, form a 3 to6-membered carbocyclic ring.
 4. The compound according to claim 1,wherein X¹ is CR⁶, where R⁶ is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, orC₁₋₄ alkoxyalkyl.
 5. The compound according to claim 1, wherein X³ is N.6. The compound according to claim 1, wherein the

moiety is selected from

R^(6a) is each independently halo, cyano, hydroxyl, amino, C₁₋₆ alkyl,alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,haloalkoxyalkyl, alkoxy, or haloalkoxy; and d is an integer of 0, 1, or2.
 7. The compound according to claim 6, wherein the

moiety is selected from

R⁶ is each independently hydrogen, halo, cyano, hydroxyl, amino, C₁₋₆alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl,haloalkoxyalkyl, alkoxy, or haloalkoxy.
 8. The compound according toclaim 1, wherein f is 0 or
 1. 9. A pharmaceutical composition comprisingone or more compounds according to claim 1, or a stereoisomer, tautomer,or pharmaceutically acceptable salt or solvate thereof; and apharmaceutically acceptable carrier or diluent.
 10. A pharmaceuticalcomposition comprising one or more compounds according to claim 6, or astereoisomer, tautomer, or pharmaceutically acceptable salt or solvatethereof; and a pharmaceutically acceptable carrier or diluent.
 11. Apharmaceutical composition comprising one or more compounds according toclaim 7, or a stereoisomer, tautomer, or pharmaceutically acceptablesalt or solvate thereof; and a pharmaceutically acceptable carrier ordiluent.
 12. A pharmaceutical composition comprising one or morecompounds according to claim 8, or a stereoisomer, tautomer, orpharmaceutically acceptable salt or solvate thereof; and apharmaceutically acceptable carrier or diluent.
 13. A method of treatinga disease, disorder, or condition associated with dysregulation oflysophosphatidic acid receptor 1 (LPA1) in a patient having the disease,disorder, or condition, comprising administering a therapeuticallyeffective amount of a compound according to claim 1, or a stereoisomer,a tautomer, or a pharmaceutically acceptable salt or solvate thereof, tothe patient.
 14. The method according to claim 13, wherein the disease,disorder, or condition is pathological fibrosis, transplant rejection,cancer, osteoporosis, or inflammatory disorders.
 15. The methodaccording to claim 14, wherein the pathological fibrosis is pulmonary,liver, renal, cardiac, dermal, ocular, or pancreatic fibrosis.
 16. Themethod according to claim 14, wherein the disease, disorder, orcondition is idiopathic pulmonary fibrosis (IPF), non-alcoholicsteatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD),chronic kidney disease, diabetic kidney disease, and systemic sclerosis.17. The method according to claim 14, wherein the cancer is of thebladder, blood, bone, brain, breast, central nervous system, cervix,colon, endometrium, esophagus, gall bladder, genitalia, genitourinarytract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral ornasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine,large intestine, stomach, testicle, or thyroid.
 18. A method of treatingfibrosis in a mammal having fibrosis, comprising administering atherapeutically effective amount of a compound according to claim 1, ora stereoisomer, a tautomer, or a pharmaceutically acceptable salt orsolvate thereof, to the mammal.
 19. The method according to claim 18,wherein the fibrosis is idiopathic pulmonary fibrosis (IPF),nonalcoholic steatohepatitis (NASH), chronic kidney disease, diabetickidney disease, and systemic sclerosis.
 20. A method of treating adisease, disorder, or condition selected from: lung fibrosis (idiopathicpulmonary fibrosis), asthma, chronic obstructive pulmonary disease(COPD), renal fibrosis, acute kidney injury, chronic kidney disease,liver fibrosis (non-alcoholic steatohepatitis), skin fibrosis, fibrosisof the gut, breast cancer, pancreatic cancer, ovarian cancer, prostatecancer, glioblastoma, bone cancer, colon cancer, bowel cancer, head andneck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia,cancer pain, tumor metastasis, transplant organ rejection, scleroderma,ocular fibrosis, age related macular degeneration (AMD), diabeticretinopathy, collagen vascular disease, atherosclerosis, Raynaud’sphenomenon, or neuropathic pain in a mammal having the disease,disorder, or condition, comprising administering a therapeuticallyeffective amount of a compound according to claim 1, or a stereoisomer,a tautomer, or a pharmaceutically acceptable salt or solvate thereof, tothe mammal.